Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics

ABSTRACT

The present disclosure relates to pyridoindolone derivatives of general formula (I): 
                         
to processes for preparing the same and to their use in therapeutics.

This application is a divisional of U.S. patent application Ser. No.11/109,068 which is a continuation of International ApplicationPCT/FR2003/003110, filed Oct. 21, 2003.

The present invention relates to pyridoindolone derivatives substitutedin the 3-position by a phenyl, to their preparation and to theirapplication in therapeutics.

French Patent No. 97 08409 discloses compounds of formula:

in which:

-   -   x represents a hydrogen or chlorine atom or a methyl or methoxy        group;    -   r₁ represents a hydrogen atom or a methyl or ethyl group;    -   r₂ represents a methyl or ethyl group; or else    -   r₁ and r₂ together form a (CH₂)₃ group;    -   r₃ represents either, on the one hand, a phenyl group optionally        substituted by a halogen atom or a methyl or methoxy group or,        on the other hand, a thienyl group.

In the description of this patent, it is mentioned that the compounds offormula (A), which have an affinity for the omega modulatory sitesassociated with GABA_(A) receptors, can be used in the treatment ofconditions related to disorders of GABAergic transmission associatedwith GABA_(A) receptor subtypes, such as anxiety, sleep disorders,epilepsy, and the like.

A subject-matter of the present invention is compounds having ananticancer activity corresponding to the formula:

in which:

-   -   R₁ represents a hydrogen atom, a (C₁-C₄)alkyl group or a        (CH₂)_(n)OH, (CH₂)_(n)—O-tetrahydropyran-2-yl, (CH₂)_(n)NR′₆R′₇,        (CH₂)_(n)CN, (CH₂)_(n)CO₂(C₁-C₄)alk or (CH₂)_(n)CONR₆R₇ group;    -   R₂ represents a hydrogen atom or a (C₁-C₄)alkyl group;    -   or R₁ and R₂ together form a (CH₂)₃ group;    -   R₃ represents a phenyl monosubstituted by a hydroxyl,        hydroxymethyl, carboxyl, (C₁-C₄)alkanoyl, azido,        (C₁-C₄)alkoxycarbonyl, hydroxyiminomethyl,        (C₁-C₄)alkylsulphonyl, trifluoromethyl, thiol, (C₁-C₄)alkylthio        or cyano group or by a (CH₂)_(m)NR′₇R₁₀, CONR₆R₈ or O(CH₂)_(n)R₉        group; a phenyl substituted by 2 to 5 identical or different        substituents chosen from a halogen atom, a (C₁-C₄)alkyl,        trifluoromethyl, hydroxyl, hydroxymethyl, (C₁-C₄)alkoxy,        carboxyl, (C₁-C₄)alkanoyl, azido, (C₁-C₄)alkoxycarbonyl,        hydroxyiminomethyl, thiol, (C₁-C₄)alkylthio or        (C₁-C₄)alkylsulphonyl group, or a phenyl or cyano, or by a        (CH₂)_(m)NR′₇R₁₀, CONR₆R₈ or O(CH₂)_(n)R₉ group; or R₃        represents a benzodioxolyl group which is unsubstituted or        substituted on the phenyl by a halogen atom;    -   R₄ and R₅ are identical or different and each independently        represent a hydrogen or halogen atom or a hydroxyl,        (C₁-C₄)alkyl, trifluoromethyl, phenyl, cyano, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxycarbonyl or (C₁-C₄)alkylsulphonyl group or an        O—(CH₂)_(n)NR₆R₇ or (CH₂)_(n)NR₆R₇ group;    -   R₆ represents hydrogen or a (C₁-C₄)alkyl group;    -   R₇ represents hydrogen or a (C₁-C₄)alkyl group;    -   or R₆ and R₇, together with the nitrogen atom to which they are        bonded, form a heterocyclic radical chosen from: piperidyl,        morpholinyl, pyrrolidinyl, piperazinyl or        4-methylpiperazin-1-yl;    -   R′₆ represents hydrogen or a (C₁-C₄)alkyl group;    -   R′₇ represents hydrogen or a (C₁-C₄)alkyl group;    -   or R′₆ and R′₇, together with the nitrogen atom to which they        are bonded, form a heterocyclic radical chosen from morpholinyl        or pyrrolidinyl;    -   R₈ represents hydrogen, a (C₁-C₄)alkyl group or a        —(CH₂)_(n)NR₆R₇ group;    -   or R₆ and R₈, together with the nitrogen atom to which they are        bonded, form a heterocyclic radical chosen from: piperidyl,        morpholinyl, pyrrolidinyl, piperazinyl or        4-methylpiperazin-1-yl;    -   R₉ represents a phenyl radical or an amino, morpholin-4-yl,        cyano or (C₁-C₄)alkoxycarbonyl group;    -   R₁₀ represents R′₆ or a phenyl, pyridyl or pyrimidinyl group or        a (CH₂)_(n)NR′₆R′₇ group;    -   or R′₁₇ and R₁₀, together with the nitrogen atom to which they        are bonded, form a heterocyclic radical chosen from piperazinyl        or 4-methylpiperazin-1-yl;    -   n represents 1, 2 or 3;    -   m represents 0 or 1;    -   Alk represents an alkyl.

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids but the salts of other useful acids, for example for thepurification or isolation of the compounds of formula (I), also formpart of the invention.

The compounds of formula (I) can also exist in the form of hydrates orof solvates, namely in the form of associations or combinations with oneor more water molecules or with a solvent. Such hydrates and solvatesalso form part of the invention.

In the context of the present invention:

-   -   a halogen atom is understood to mean: a fluorine, a chlorine, a        bromine or an iodine;    -   a (C₁-C₄)alkyl group is understood to mean: a saturated, linear        or branched, aliphatic group comprising 1 to 4 carbon atoms.        Mention may be made, by way of example, of the methyl, ethyl,        propyl, butyl, isobutyl and tert-butyl groups;    -   a (C₁-C₄)alkoxy group is understood to mean: an O-alkyl radical        where the alkyl group is as defined above.

A subject-matter of the present invention is very particularly compoundsof formula (I) in which:

-   -   R₁ represents a hydrogen atom, a (C₁-C₄)alkyl group or a        (CH₂)_(n)CO₂(C₁-C₄)alk or (CH₂)_(n)CONR₆R₇ group;    -   R₂ represents a hydrogen atom or a (C₁-C₄)alkyl group;    -   R₃ represents a phenyl monosubstituted by a hydroxyl,        hydroxymethyl, carboxyl, (C₁-C₄)alkoxycarbonyl,        hydroxyiminomethyl, (C₁-C₄)alkylsulphonyl, trifluoromethyl,        thiol, (C₁-C₄)alkylthio or cyano group or by a (CH₂)_(m)NR₆R₇ or        CONR₆R₈ group; a phenyl substituted by 2 to 5 identical or        different substituents chosen from a halogen atom or a        (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, hydroxymethyl,        (C₁-C₄)alkoxy, carboxyl, (C₁-C₄)alkoxycarbonyl,        hydroxyiminomethyl, thiol, (C₁-C₄)alkylthio,        (C₁-C₄)alkylsulphonyl or cyano group or by a (CH₂)_(m)NR₆R₇ or        CONR₆R₈ group; or R₃ represents a benzodioxolyl group;    -   R₄ and R₅ are identical or different and each independently        represent a hydrogen or halogen atom or a hydroxyl,        (C₁-C₄)alkyl, trifluoromethyl, cyano, (C₁-C₄)alkoxy or        (C₁-C₄)alkoxycarbonyl group or an O—(CH₂)_(n)NR₆R₇ group;    -   R₆ represents hydrogen or a (C₁-C₄)alkyl group;    -   R₇ represents hydrogen or a (C₁-C₄)alkyl group;    -   or R₆ and R₇, together with the nitrogen atom to which they are        bonded, form a heterocyclic radical chosen from: piperidyl,        morpholinyl, pyrrolidinyl, piperazinyl or        4-methylpiperazin-1-yl;    -   R₈ represents hydrogen, a (C₁-C₄)alkyl group or a        —(CH₂)_(n)NR₆R₇ group;    -   or R₆ and R₈, together with the nitrogen atom to which they are        bonded, form a heterocyclic radical chosen from: piperidyl,        morpholinyl, pyrrolidinyl, piperazinyl or        4-methylpiperazin-1-yl;    -   n represents 1, 2 or 3;    -   m represents 0 or 1;    -   Alk represents an alkyl.

Mention may be made, among the compounds of formula (I) which aresubject-matters of the invention, of the preferred compounds which aredefined as follows:

-   -   R₁ represents a hydrogen atom or a methyl, cyanomethyl,        (C₁-C₄)alkoxycarbonylmethyl, aminomethyl, aminoethyl,        aminopropyl or pyrrolidinoethyl group;    -   and/or R₂ represents a methyl group;    -   and/or R₁ and R₂ together form a (CH₂)₃ group;    -   and/or R₃ represents a phenyl monosubstituted by a hydroxyl,        (C₁-C₄)alkoxycarbonyl, methylsulphonyl, trifluoromethyl,        methylthio, cyanomethoxy, aminoethoxy, acetyl, hydroxymethyl,        cyano, amino, azido, aminomethyl or hydroxyiminomethyl group or        a (CH₂)_(m)NR′₇R₁₀ group in which R′₇ represents a hydrogen atom        or a methyl, R₁₀ represents a hydrogen atom or a phenyl, pyridyl        or pyrimidinyl group or R′₇ and R₁₀, together with the nitrogen        atom to which they are bonded, form a piperazin-1-yl or        4-methylpiperazin-1-yl group, and m represents zero or one; or        R₃ represents a phenyl substituted by 2 to 3 identical or        different substituents chosen from a halogen atom, a methyl,        methoxy, methylthio, trifluoromethyl, hydroxyl,        (C₁-C₄)alkoxycarbonyl, methylsulphonyl, cyanomethoxy,        aminoethoxy, acetyl, hydroxymethyl, cyano, amino, azido,        aminomethyl or hydroxyiminomethyl group or a (CH₂)_(m)NR′₇R₁₀        group in which R′₇ represents a hydrogen atom or a methyl, R₁₀        represents a hydrogen atom or a phenyl, pyridyl or pyrimidinyl        group or R′₇ and R₁₀, together with the nitrogen atom to which        they are bonded, form a piperazin-1-yl or 4-methylpiperazin-1-yl        group, and m represents zero or one; or R₃ represents a        benzodioxolyl group which is unsubstituted or substituted on the        phenyl by a halogen atom;    -   and/or R₄ represents a halogen atom or a methyl, methoxy or        (C₁-C₄)alkoxycarbonyl group;    -   and/or R₅ represents a hydrogen atom or a methyl group.

Preference is very particularly given to the following compounds:

-   -   3-(2,4-dimethoxyphenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylic        acid;    -   3-(2,4-dimethoxyphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   3-(3-hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]-indol-3-yl)benzonitrile;    -   3-(4-aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   3-(6-chloro-1,3-benzodioxol-5-yl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   1,6-dimethyl-1,9-dihydro-3-(phenylaminophenyl)-2H-pyrido[2,3-b]indol-2-one;    -   6-bromo-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   1,6-dimethyl-3-(3-(trifluoromethyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   1,6-dimethyl-3-(3-(pyridin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   1,6-dimethyl-3-(3-(pyrimidin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   3-(3-acetylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;    -   2-(2,4-dichlorophenyl)-9-methyl-5,6-dihydro-3H,4H-3a,6a-diazafluoranthen-3-one;    -   methyl        9-(cyanomethyl)-3-(2,4-dichlorophenyl)-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylate;        and their addition salts, their solvates and their hydrates.

In that which follows, protective group Gp or G′p is understood to meana group which makes it possible, first, to protect a reactive functionalgroup, such as a hydroxyl or an amine, during a synthesis and, secondly,to regenerate the intact reactive functional group at the end of thesynthesis. Examples of protective groups and methods for protection anddeprotection are given in “Protective Groups in Organic Synthesis”,Green et al., 2^(nd) Edition (John Wiley & Sons Inc., New York).

The term “leaving group” is understood to mean, in that which follows, agroup which can be easily cleaved from a molecule by splitting aheterolytic bond, with departure of an electron pair. This group canthus be easily replaced by another group during a substitution reaction,for example. Such leaving groups are, for example, halogens or anactivated hydroxyl group, such as a mesyl, tosyl, triflate, acetyl, andthe like. Examples of leaving groups and references for theirpreparation are given in “Advances in Organic Chemistry”, J. March,3^(rd) Edition, Wiley Interscience, p. 310-316.

In accordance with the invention, the compounds of general formula (I)can be prepared according to the following process.

This process is characterized in that: a 2-aminoindole of formula:

in which R₁, R₂, R₄ and R₅ are as defined for a compound of formula (I),is reacted with an ester of formula:

in which R₃ is as defined for a compound of formula (I) and Alkrepresents a C₁-C₄ alkyl.

The reaction is carried out in a polar and preferably basic solvent, forexample in pyridine, at a temperature of between ambient temperature andthe reflux temperature of the solvent.

Generally, it is also possible to prepare, according to the process ofthe invention, a compound of formula:

in which the R′₁, R′₂, R′₃, R′₄ and R′₅ substituents are precursors ofthe R₁, R₂, R₃, R₄ and R₅ substituents as defined for a compound offormula (I), and then, by using methods known to a person skilled in theart, to convert these substituents in order to obtain the R₁, R₂, R₃, R₄and R₅ substituents desired for the compound of formula (I).

A compound of formula (I) in which R₁ and/or R₂ is an alkyl group isprepared from a compound of formula (I) in which R₁ or R₂ is hydrogen bythe action of an alkyl iodide in the presence of NaH.

The compounds of formula (I) in which the R₁ substituent is a—(CH₂)_(n)CO₂(C₁-C₄)Alk or —(CH₂)_(n)CONR₆R₇ group are prepared from thecorresponding compounds of formula (I)′ in which R₁═H and R₂, R₃, R₄ andR₅ have the same values.

For example, a compound of formula (I) in which R₁═H can be substitutedby a (CH₂)₂CN group by reacting with a compound of formula Br(CH₂)_(n)CNin the presence of sodium hydride.

Furthermore, in order to prepare a compound of formula (I) in which R₁represents a (CH₂)_(n)NR′₆R′₇ group, a brominated compound of formulaBr(CH₂)_(n)NR′₆R′₇ can be reacted with a compound of formula (I) inwhich R₁═H.

More generally, in order to prepare a compound of formula (I) in whichR₁ represents a (CH₂)_(n)NR′₆R′₇ group, a compound of formulaX(CH₂)_(n)NGp in which X represents a leaving group, such as a bromineatom or a mesyl or tosyl group, for example, and Gp represents aprotective group for the nitrogen can be reacted with a compound offormula (I) in which R₁═H; after deprotection of the nitrogen, it ispossible, if appropriate, to alkylate the amine formed by using methodsknown to a person skilled in the art.

To prepare a compound of formula (I) in which R₁ represents a(CH₂)_(n)OH group, a compound of formula X(CH₂)_(n)O-G′p in which X is aleaving group and G′p is a protective group for the oxygen can bereacted with a compound of formula (I) in which R₁═H and then thecompound thus obtained can be treated to remove the protective group bymethods known to a person skilled in the art.

To prepare a compound of formula (I) in which the R₃ and/or R₄ and/or R₅substituents comprise a hydroxymethyl, hydroxyiminomethyl,alkylaminomethyl or dialkylaminomethyl group, the corresponding compoundof formula (I) carrying an R₃ and/or R₄ and/or R₅ substituent comprisinga cyano group is converted by methods known to a person skilled in theart.

To prepare a compound of formula (I) in which the R₃ and/or R₄ and/or R₅substituents comprise a hydroxyl group, it is possible to prepare firstan analogous compound of formula (I) in which the R₃ and/or R₄ and/or R₅substituents comprise a protected hydroxyl group and then, in asubsequent stage, to convert this group to a hydroxyl by methods knownto a person skilled in the art. Use may be made, as protective group forthe hydroxyl, of a benzyl, a benzoyl or a (C₁-C₄)alkyl, for example.

The compounds of formula (I) in which R₄ and/or R₅ represent a Br atomor the substituent(s) on the R₃ phenyl group represent(s) one (orseveral) bromine atom(s) can be used as precursors for preparing othercompounds according to the invention, for example compounds carryingamine substituents, such as (CH₂)_(n)NR₆R₇ or (CH₂)_(n)NR′₇R₁₀, by usingreactions known to a person skilled in the art.

Compounds carrying a brominated substituent are also of use for thepreparation of compounds carrying an alkoxycarbonyl substituent.

The aminoindoles of formula (II) can be prepared by methods such asthose described in Khim. Geterosikl. Soedin., 1973, 12, 647-652 and inJ. Heterocycl. Chem., 1975, 12, 135-138.

Some 2-aminoindole derivatives of formula (II) are known and aredescribed in Khim. Geterosikl. Soedin., 1973, 4, 511-515; Eur. J. Med.Chem. Chim. Ther., 1992, 27 (9), 908-918; Chem. Heterocycl. Compd.(Engl. Transl.), 1970, 6, 338-343; Tetrahedron, 1971, 27, 775-785;Pharm. Chem. J. (Engl. Transl.), 1990, 24 (11), 810-812; TetrahedronLett., 1996, 37 (28), 4931-4932.

Some esters of formula (III) are known and can be prepared by methodssuch as those described in J. Org. Chem., 1984, 49 (22), 4287-4290; J.Am. Chem. Soc., 1974, 96 (7), 2121; Tetrahedron, 1970, 26 (2), 715-719;Synth. Commun., 2000, 30 (8), 1401-1411; Zhongguo Yaowu Huaxue Zazhi,2000, 10 (1), 9-12, 25; JP 19 680 131, EP 260 832, EP 178 826, WO 97-46577, DE 3 221 915.

The compounds according to the invention can also be prepared by aprocess characterized in that: an aminoindole of formula:

in which R₁, R₂, R₄ and R₅ are as defined for a compound of formula (I),is reacted with an ester of formula:

in which R₃ is as defined for a compound of formula (I) and Alkrepresents a C₁-C₄ alkyl.

The reaction is carried out in a protic and polar solvent, preferably inan acidic medium, at a temperature of between ambient temperature andthe reflux temperature of the solvent.

The compound of formula (IV) is prepared usingdimethoxy-N,N-dimethylmethanamine (V) by a method similar to thatdescribed in J. Org. Chem., 1982, 47, 2846-2851 or using Bredereck'sreagent (tert-butoxybis(dimethylamino)methane) according to J. Org.Chem., 1982, 15, 2846-2851 and according to the following reactionscheme:

Unless otherwise indicated, the proton nuclear magnetic resonance (NMR)spectra are recorded in d₆-DMSO; the reference is placed in the d₆-DMSO,which lies at 2.50 ppm from the tetramethylsilane.

The signals observed by NMR spectroscopy are expressed thus: s: singlet;bs: broad singlet; d: doublet; sd: split doublet; t: triplet; st: splittriplet; q: quartet; mt: multiplet.

The preparation of some compounds in accordance with the invention isdescribed in the following examples. These examples are not limiting andserve only to illustrate the present invention. The numbers of thecompounds in the examples refer to those given in the table below, inwhich the chemical structures and the physical properties of a fewcompounds according to the invention are illustrated.

In the preparations and examples which will follow, the followingabbreviations are used:

-   -   TEA: triethylamine    -   DMA: dimethylacetamide    -   DMF: dimethylformamide    -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene    -   LAH: LiAlH₄: lithium aluminium hydride    -   NMP: N-methylpyrrolidin-2-one    -   LiN(TMS)₂: lithium bis(trimethylsilyl)amide    -   DCM: dichloromethane    -   AcOEt: ethyl acetate    -   AcOH: acetic acid    -   NBS: N-bromosuccinimide    -   AIBN: 2,2′-azobisisobutyronitrile    -   Xant phos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene    -   Pd(dba)₃: tris(dibenzylideneacetone)dipalladium    -   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   MTBE: methyl tert-butyl ether    -   MiBK: methyl isobutyl ketone    -   Bredereck's reagent: tert-butoxybis(dimethylamino)methane    -   AT: ambient temperature

Preparation of the Compounds of Formula (II)

The compounds of formula (II) can exist in two tautomeric forms:

Preparation 1.1 N,1,5-Trimethyl-1H-indole-2-amine hydrochloride A)N′-(4-Methylphenyl)acetohydrazide

104.8 g of 1-(4-methylphenyl)hydrazine hydrochloride are suspended in525 ml of isopropyl acetate, a solution of 104.8 g of potassiumcarbonate in 300 ml of water is added and then the mixture is stirreduntil the solid has disappeared. 77.4 g of acetic anhydride are addedwhile maintaining the temperature below 20° C. and then the mixture isleft stirring at 20° C. A precipitate is observed to form, whichprecipitate disappears when the mixture is heated at approximately55-60° C. The organic phase is washed twice with 200 ml of water and isthen cooled at 0-5° C. overnight. The product formed is recovered byfiltration and is then washed twice with 100 ml of MTBE.

NMR CDCl₃ (300 MHz): 2.02 ppm: s: 3H; 2.29 ppm: s: 3H; 6.14 ppm: d: 1H;6.73 ppm: d: 2H; 7.03 ppm: d: 2H; 7.72 ppm: s: 1H.

B) N,N′-Dimethyl-N′-(4-methylphenyl)acetohydrazine

60 g of hydrazine from the preceding stage and 11.8 g oftetrabutylammonium bromide are suspended in 240 ml of toluene, and 292 gof 50% NaOH in water and then 155.6 g of methyl iodide are added. 83 gof sodium hydroxide pellets are then added and then the reaction mediumis heated at 80° C. for 6 hours. The mixture is cooled to 30-35° C. andthen 500 ml of water are added. The organic phase is washed three timeswith 100 ml of water. The organic phase is dried by azeotropicdistillation of the water under reduced pressure.

NMR CDCl₃ (300 MHz): 2.15 ppm: s: 3H; 2.31 ppm: s: 3H; 2.95 ppm: s: 3H;3.10 ppm: s: 3H; 6.63 ppm: d: 2H; 7.13 ppm: d: 2H.

C) N,1,5-Trimethyl-1H-indole-2-amine hydrochloride

The product obtained in the preceding stage is dissolved in toluene,61.5 g of phosphorus oxychloride are added and the mixture is heated at80° C. for 2 hours. 100 ml of ethyl acetate are added at 80° C. and thenthe medium is cooled to AT. The precipitate is filtered off and thenwashed twice with 50 ml of ethyl acetate, m.p.=222° C.

NMR d₆-DMSO (200 MHz): 2.36 ppm: s: 3H; 3.11 ppm: s: 3H; 3.49 ppm: s:3H; 4.29 ppm: s: 1H; 7.25-7.35 ppm: unresolved peak: 3H; 10.07 ppm:unresolved peak: 1H.

Preparation 1.2 N,5-Dimethyl-1H-indole-2-amine dihydrochloride A)N′-(4-Methylphenyl)acetohydrazide

Another process for the preparation of this compound is described below.

5 g of 1-(4-methylphenyl)hydrazine hydrochloride are dissolved in waterand then triethylamine is added until the salt has been neutralized.Extraction is carried out with AcOEt and then the extract is evaporatedto dryness. The precipitate formed is dissolved in 30 ml of ether andthen a solution of 4.6 ml of acetic anhydride dissolved in 30 ml ofether is added dropwise. The mixture is stirred at 0° C. for 15 minutesand then the precipitate formed is filtered off to produce 3 g of theexpected compound.

NMR CDCl₃ (300 MHz): 2.02 ppm: s: 3H; 2.29 ppm: s: 3H; 6.14 ppm: d: 1H;6.73 ppm: d: 2H; 7.03 ppm: d: 2H; 7.72 ppm: s: 1H.

B) N-Methyl-N′-(4-methylphenyl)acetohydrazide

0.8 g of 60% NaH is suspended in 30 ml of DMF. 3.2 g of hydrazineobtained in the preceding stage in 20 ml of DMF are added dropwise at 0°C. When gas evolution has ceased, 1.8 ml of methyl iodide are added andthe mixture is stirred at AT for one hour. The mixture is poured onto asaturated NH₄Cl solution and then extraction is carried out with AcOEt.Washing is carried out several times with a saturated NaCl solution andthen evaporation is carried out to dryness. The residue is purified bychromatography on a silica column eluted with an AcOEt/heptane mixture,(25/75; v/v) then (50/50; v/v), to produce 1.0 g of the expectedcompound in the form of a white powder.

NMR CDCl₃ (200 MHz): 2.21 ppm: s: 3H; 2.32 ppm: s: 3H; 3.15 ppm: s: 3H;5.88 ppm: s: 1H; 6.64 ppm: d: 2H; 7.12 ppm: d: 2H.

C) N,5-Dimethyl-1H-indole-2-amine dihydrochloride

1.0 g of the compound from the preceding stage is dissolved in 20 ml ofPOCl₃ and then the mixture is heated at 100° C. for two hours. Thereaction mixture is cooled and then ether is added. The precipitateformed is filtered off and is washed with ether to produce 1.3 g of theexpected compound.

NMR d₆-DMSO (300 MHz): 2.31 ppm: s: 3H; 3.05 ppm: s: 3H; 4.14 ppm: s:2H; 7.07-7.23 ppm: unresolved peak: 3H; 10.51 ppm: s: 1H; 12.37 ppm: d:1H.

Preparation 1.3 N,1-Dimethyl-5-methoxy-1H-indole-2-amine hydrochlorideA) N′-(4-Methoxyphenyl)acetohydrazide

10 g of 4-methoxyphenylhydrazine hydrochloride are dissolved in waterand then triethylamine is added until the salt has been neutralized.Extraction is carried out with AcOEt and then the extract is evaporatedto dryness to produce 8 g of precipitate composed of4-methoxyphenylhydrazine. This compound is dissolved in 30 ml of etherand then a solution of 13 ml of acetic anhydride dissolved in 30 ml ofether is added dropwise. The mixture is stirred at 0° C. for 15 minutesand then the white precipitate formed is filtered off to produce 7.4 gof the expected compound.

NMR CDCl₃ (200 MHz): 2.06 ppm: s: 3H; 3.75 ppm: s: 3H; 5.65 and 6.03ppm: 2s: 2H; 6.6-6.9 ppm: unresolved peak: 4H.

B) N,N′-Dimethyl-N′-(4-methoxyphenyl)acetohydrazide

4.3 g of 60% NaH are suspended in 30 ml of DMA. 7.4 g of the compoundfrom the preceding stage, dissolved in 20 ml of DMA, are added dropwise.When gas evolution has ceased, 10.0 ml of iodomethane are added. Themixture is stirred at ambient temperature for one hour. It is pouredonto a saturated NH₄Cl solution and then extraction is carried out withAcOEt. The organic phase is washed several times with a saturated NaClsolution and is then evaporated to dryness. The residue obtained istriturated in petroleum ether to produce 8.0 g of the expected compoundin the form of an oil.

NMR CDCl₃ (200 MHz): 2.19 ppm: s: 3H; 2.93 ppm: s: 3H; 3.08 ppm: s: 3H;3.80 ppm: s: 3H; 6.68 ppm: d: 2H; 6.89 ppm: d: 2H.

C) N,1-Dimethyl-5-methoxy-1H-indole-2-amine hydrochloride

8.0 g of the compound from the preceding stage are dissolved in 30 ml ofPOCl₃ and then the mixture is heated at 80° C. for 2 hours. The reactionmixture is cooled and then ether is added. The brown precipitate formedis filtered off and washed with ether to produce 5.3 g of the expectedcompound, m.p.=222° C.

NMR d₆-DMSO (300 MHz): 3.06 ppm: s: 3H; 3.48 ppm: s: 3H; 3.76 ppm: s:3H; 4.26 ppm: s: 2H; 6.96-7.00 ppm: dd: 1H; 7.14 ppm: d: 1H; 7.24 ppm:d: 1H; 10.08 ppm: s: 1H.

Preparation 1.4 N,1-Dimethyl-5-chloro-1H-indole-2-amine hydrochloride A)N′-(4-Chlorophenyl)acetohydrazide

12.5 g of 4-chlorophenylhydrazine hydrochloride are dissolved in 100 mlof water and then triethylamine is added until the salt has beenneutralized. Extraction is carried out with AcOEt and then the extractis evaporated to dryness. The base is dissolved in 100 ml of ether, thesolution is cooled to 0° C. and then 15 ml of acetic anhydride are addeddropwise. The mixture is stirred at 0° C. for 15 minutes. The whiteprecipitate formed is filtered off and is then washed with ether toproduce 12.8 g of the expected compound in the form of a white powder.

NMR CDCl₃ (200 MHz): 2.09 ppm: s: 3H; 6.68-6.86 ppm: unresolved peak:2H; 7.12-7.30 ppm: unresolved peak: 2H.

B) N,N′-Dimethyl-N′-(4-chlorophenyl)acetohydrazide

7.2 g of 60% NaH are suspended in 30 ml of DMA. 12.8 g of hydrazine fromthe preceding stage, dissolved in 50 ml of DMA, are added dropwise andthe mixture is stirred at ambient temperature until gas evolution hasceased. 17 ml of iodomethane are added dropwise and the mixture isstirred at ambient temperature for one hour. The mixture is poured ontoa saturated NH₄Cl solution and then extraction is carried out withAcOEt. The organic phase is washed with a saturated NaCl solution. Theresidue obtained is triturated with petroleum ether to produce 10 g ofthe expected compound in the crystalline form.

NMR CDCl₃ (200 MHz): 2.10 ppm: s: 3H; 2.95 ppm: s: 3H; 3.10 ppm: s: 3H;6.62 ppm: d: 2H; 7.24 ppm: d: 2H.

C) N,1-Dimethyl-5-chloro-1H-indole-2-amine hydrochloride

10 g of the compound from the preceding stage are dissolved in 50 ml ofPOCl₃. The mixture is heated at reflux for two hours. The reactionmedium is cooled, ether is added and then the product obtained isfiltered off. The precipitate is washed several times with ether toproduce 9.6 g of the expected compound in the form of a powder.

NMR d₆-DMSO (300 MHz): 3.08 ppm: s: 3H; 3.52 ppm: s: 3H; 4.31 ppm: s:2H; 7.34 ppm: d: 1H; 7.48 ppm: d: 1H; 7.60 ppm: s: 1H; 10.61 ppm: s: 1H.

Preparation 1.5 Methyl 1-methyl-2-(methylamino)-1H-indole-5-carboxylateA) Methyl 4-(2-acetylhydrazino)benzoate

5.5 g of methyl 4-hydrazinobenzoate are dissolved in 38.2 ml of AcOHcomprising 2.4 g of sodium acetate and the mixture is heated at 80° C.for 18 hours. The inorganic material is filtered off, the filtrate isthen evaporated and the residue is taken up in the minimum amount ofEt₂O. The mixture is filtered to produce 7.97 g of the expectedcompound.

B) Methyl 4-(2-acetyl-1,2-dimethylhydrazino)benzoate

2.95 g of 95% NaH are suspended in 90 ml of DMF, 8.135 g of the compoundfrom the preceding stage, in solution in the minimum amount of DMF, areadded dropwise and then, after a few minutes, 9.75 ml of methyl iodideare added dropwise. The mixture is stirred at AT for one hour. Themedium is poured onto a saturated NH₄Cl solution and extraction iscarried out with AcOEt. The organic phase is washed with NaCl, dried andevaporated to give 5.4 g of the expected compound.

C) Methyl 1-methyl-2-(methylamino)-1H-indole-5-carboxylate

5.4 g of the compound from the preceding stage and 62 ml of phosphorusoxychloride are mixed and the mixture is heated at 80° C. for two and ahalf hours. The medium is evaporated and the residue is taken up inAcOEt. The solid formed is filtered off, washed with AcOEt and dried togive 4 g of the expected compound.

NMR MeOD (250 MHz): 3.2 ppm: s: 3H; 3.6 ppm: s: 3H; 3.9 ppm: s: 3H;7.3-7.4 ppm: unresolved peak: 2H; 8.1-8.2 ppm: unresolved peak: 2H.

The compounds of formula (II) collated in the table below are preparedby operating as described above:

TABLE 1 (II)

Characterization Preparation R₁ R₄, R₅ M.p. (° C.) or NMR 1.6 Me H 249°C. 1.7 Me 7-OMe 284° C. 1.8 Me 4-OMe 103° C. 1.9 Me 6-OH 103° C. 1.10 Me6-Me 1.11 Me 4,6-diMe 134° C. 1.12 Me 5-OMe 222° C. 1.13 Me 5-Cl NMR1.14 Me 6-OMe 103° C. 1.15 Me 5-CN 245° C. 1.16 Me 5-phenyl NMR 1.13d₆-DMSO (300 MHz): 3.08 ppm:d:3H; 3.52 ppm:s:3H; 7.34 ppm:d:1H; 7.48ppm:d:1H; 7.60 ppm:s:1H; 10.61 ppm:s:1H.

Preparation 1.17 Ethyl 2-(methylimino)indoline-5-carboxylatehydrochloride A) Ethyl 4-hydrazinobenzoate

5.0 g of 4-hydrazinobenzoic acid are dissolved in 70 ml of ethanol and 3ml of concentrated H₂SO₄. The mixture is heated at reflux for fivehours, the ethanol is evaporated, the residue is then taken up in asaturated K₂CO₃ solution and then extraction is carried out with AcOEt.5.9 g of the expected compound are obtained in the form of a powder.

NMR CDCl₃ (300 MHz): 1.38 ppm: t: 3H; 3.65 ppm: s: 2H; 4.34 ppm: q: 2H;5.57 ppm: s: 1H; 6.80 ppm: d: 2H; 7.93 ppm: d: 2H.

B) Ethyl 4-(N′-acetylhydrazino)benzoate

5.9 g of the compound from the preceding stage are dissolved in 50 ml ofacetic acid, and 3.0 g of sodium acetate are added. The mixture isheated at 80° C. for 16 hours. The acetic acid is evaporated, theresidue is taken up in water and then extraction is carried out withCH₂Cl₂. The organic phase is dried over MgSO₄ and is then evaporated todryness. 4.2 g of powder are obtained.

NMR CDCl₃ (300 MHz): 1.36 ppm: t: 3H; 2.04 ppm: s: 3H; 4.32 ppm: q: 2H;6.63 ppm: s: 1H; 6.73 ppm: d (J=8.8): 2H; 7.88 ppm: d: 2H; 8.00 ppm: s:1H.

C) Ethyl 4-(N′-acetyl-N′-methylhydrazino)benzoate

0.72 g of 60% NaH is suspended in 20 ml of DMF. The mixture is cooled to0° C. and then 4.0 g of the compound from the preceding stage, dissolvedin 20 ml of DMA, are added. The mixture is stirred at 0° C. for 15minutes, then 1.7 ml of iodomethane are added and the mixture is stirredat 0° C. for 30 minutes. It is poured onto a saturated NH₄Cl solutionand extracted with AcOEt. The organic phase is washed with a saturatedNaCl solution, dried over MgSO₄ and then adsorbed on silica.Purification is carried out by chromatography on a silica column elutedwith an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.8 g of oil areobtained.

NMR CDCl₃ (300 MHz): 1.38 ppm: t: 3H; 2.15 ppm: s: 3H; 3.17 ppm: s: 3H;4.35 ppm: q (J=7.1): 2H; 6.10 ppm: s: 1H; 6.71 ppm: d (J=8.8): 2H; 7.99ppm: d: 2H.

D) Ethyl 2-(methylimino)indoline-5-carboxylate hydrochloride

1.5 g of the compound from the preceding stage are dissolved in 10 ml ofPOCl₃. The mixture is heated at 80° C. for two hours. The reactionmedium is cooled, ether is added and the precipitate formed istriturated and filtered off. It is washed with ether. 1.4 g of powderare obtained.

NMR CDCl₃ (300 MHz): 1.31 ppm: t (J=7.1): 3H; 3.07 ppm: d (J=4.7): 3H;4.25 ppm: s: 2H; 4.31 ppm: q: 2H; 7.58 ppm: d (J=8.8): 1H; 7.99 ppm:unresolved peak: 2H; 10.97 ppm: s: 1H; 12.81 ppm: s: 1H.

Preparation 1.18 5-Bromo-N-methyl-1H-indole-2-amine hydrochloride A)N′-(4-Bromophenyl)formohydrazide

10.0 g of 4-bromophenylhydrazine hydrochloride are dissolved in 30 ml ofwater. 6.2 g of K₂CO₃ and 36 ml of methyl formate are added and then themixture is heated at reflux for one hour and then at ambient temperaturefor 12 hours. The precipitate formed is filtered off and washed with anisopropanol/petroleum ether (v/v; 50/50) mixture. 10.5 g of the expectedproduct are obtained.

NMR CDCl₃ (300 MHz) 6.73-6.77 ppm: unresolved peak: 2H; 7.34-7.41 ppm:unresolved peak: 2H; 8.33 ppm: unresolved peak: 1H.

B) N′-(4-Bromophenyl)-N-methylacetohydrazide

A solution of 80 ml of LAH in THF is heated to reflux. 10.5 g of thecompound from the preceding stage, in suspension in 60 ml of THF, areadded. The mixture is heated at reflux for 15 hours. The reaction mediumis cooled and then 2.3 ml of water, then 9.0 ml of 1N NaOH and thenagain 10 ml of H₂O are added dropwise. The salts are filtered offthrough Celite®, washing is carried out with AcOEt and then evaporationto dryness is carried out. The residue is taken up in 80 ml of AcOEt,then 17 g of K₂CO₃, dissolved in 80 ml of water, are added, followed by4.0 ml of acetic anhydride. The mixture is stirred at ambienttemperature for one hour. The two phases are separated and the organicphase is dried over MgSO₄ and then evaporated to dryness. Petroleumether is added and then the crystals formed are filtered off. 9.0 g ofthe expected product are obtained.

NMR CDCl₃ (300 MHz): 2.15 ppm: s: 3H; 3.13 ppm: s: 3H; 6.57-6.62 ppm:unresolved peak: 2H; 7.32-7.40 ppm: unresolved peak: 2H.

C) 5-Bromo-N-methyl-1H-indole-2-amine hydrochloride

9.0 g of hydrazine obtained in the preceding stage are dissolved in 50ml of POCl₃ and then the mixture is heated at 80° C. for two hours. Thereaction mixture is cooled and then ether is added. The precipitateformed is filtered off and washed with ether. 8.2 g of powder areobtained.

NMR CDCl₃ (300 MHz): 4.31 ppm: s: 3H; 7.14-7.87 ppm: unresolved peak:4H; 10.70 ppm: unresolved peak: 1H; 12.62 ppm: s: 1H.

Preparation 1.19 8-Methyl-1,2,3,4-tetrahydropyrimido[1,2-a]-indole A)1-(4-Methylphenyl)pyrazolidin-3-one

10 g of p-tolylhydrazine hydrochloride are dissolved in 100 ml ofanhydrous CH₂Cl₂. The solution is cooled to 0° C. and 19 ml of DBU andthen 6.5 mg of 3-bromopropionyl chloride are added. The mixture isstirred at ambient temperature for one hour. The reaction medium ispoured onto water, extraction is carried out with CH₂Cl₂ and thenpurification is carried out by chromatography on a silica column elutedwith an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.3 g of crystalsare obtained.

NMR CDCl₃ (300 MHz): 2.35 ppm: s: 3H; 2.54 ppm: t (J=7.9): 2H; 3.89 ppm:q (J=7.9) 2H; 6.93-7.16 ppm: unresolved peak: 4H; 8.22 ppm: s: 1H.

B) 1-Acetyl-2-(4-methylphenyl)pyrazolidine

1.3 g of the compound from the preceding stage, dissolved in 20 ml ofanhydrous THF, are added to 9.6 ml of a 1M solution of LAH in THF. Themixture is heated at reflux for 18 hours. It is cooled to ambienttemperature, 2 ml of water and 7 ml of 1N sodium hydroxide solution arethen added, and then the salts are filtered off through Celite®. Thefiltrate is evaporated and the residue is taken up in 20 ml of AcOEt.2.6 g of K₂CO₃ and 5 ml of H₂O are added, followed by 0.6 ml of aceticanhydride. The mixture is stirred at ambient temperature for one hour.The two phases are separated and the organic phase is dried over MgSO₄and then evaporated to dryness. 1.4 g of oil are obtained.

NMR CDCl₃ (300 MHz): 1.93-2.05 ppm: unresolved peak: 2H; 2.07 ppm: s 3H;2.30 ppm: s: 3H; 3.50 ppm: unresolved peak: 4H; 6.83-7.11 ppm unresolvedpeak: 4H.

C) 8-Methyl-1,2,3,4-tetrahydropyrimido[1,2-a]indole

1.4 g of the compound from the preceding stage are dissolved in 10 ml ofPOCl₃. The mixture is heated at 80° C. for one hour 30 minutes. Thereaction medium is cooled, ether is added and then the precipitateformed is filtered off and washed with ether. 1.4 g of the expectedcompound are obtained in the form of a powder.

NMR d₆-DMSO (300 MHz): 2.06-2.14 ppm: unresolved peak: 2H; 2.33 ppm: s:3H; 3.50 ppm: unresolved peak: 2H; 3.84-3.88 ppm: unresolved peak: 2H;4.15 ppm: s: 2H; 7.15-7.29 ppm: unresolved peak: 3H; 10.84 ppm: s: 1H.

Preparation of the Intermediates of Formulae (III) and (IV) Preparation2.1 Methyl 2-(3,5-difluorophenyl)-3-dimethylamino-2-propenoate (IV) A)Methyl (3,5-difluorophenyl)acetate

A solution comprising 25 ml of acetyl chloride in 250 ml of methanol isprepared at 0° C., then, at ambient temperature, 25.5 g of3,5-difluorophenylacetic acid are dissolved in this solution and thesolution is left stirring at AT. The reaction is monitored by thin layerchromatography. After the starting material has disappeared, the mediumis evaporated under reduced pressure and then the residue is dissolvedin 250 ml of MTBE. The organic phase is washed three times with 100 mlof water, dried over MgSO₄ and then evaporated to dryness under reducedpressure. 26.9 g of the expected compound are obtained.

B) Methyl 2-(3,5-difluorophenyl)-3-dimethylamino-2-propenoate

26.9 g of the compound from the preceding stage are dissolved in 61 mlof dimethoxy-N,N-dimethylmethanamine. The mixture is heated at 135-140°C. and the methanol formed is distilled off (12 g). The solvent isevaporated under reduced pressure and the residue is taken up in 250 mlof MTBE. The organic phase is washed three times with 50 ml of water,then dried over MgSO₄ and evaporated to dryness. The residuerecrystallizes from methylcyclohexane. The product formed is filteredoff and is then washed twice with 25 ml of methylcyclohexane to give 28g of the expected compound, M.p.=97° C.

Preparation 2.2 Ethyl 2-(3,5-difluorophenyl)-3-hydroxy-2-propenoate(III) A) Ethyl 3,5-difluorophenylacetate

5 g of 3,5-difluorophenylacetic acid are dissolved in 50 ml of ethanoland 3 ml of concentrated H₂SO₄, and the mixture is heated at reflux fortwo hours. The mixture is evaporated to dryness, neutralization is thencarried out with a saturated K₂CO₃ solution, extraction is then carriedout with AcOEt and the organic phase is evaporated to produce 5.0 g ofthe expected compound in the form of a colourless liquid.

NMR CDCl₃ (200 MHz): 1.27 ppm: t: 3H; 3.59 ppm: s: 2H; 4.18 ppm: q: 2H;6.68-6.85 ppm: unresolved peak: 3H.

B) Ethyl 2-(3,5-difluorophenyl)-3-hydroxy-2-propenoate

5.0 g of ethyl 3,5-difluorophenylacetate are dissolved in 50 ml of ethylformate. 2.0 g of 60% NaH are added portionwise. The mixture is pouredonto a 1N HCl solution and then extraction is carried out with AcOEt.The residue is triturated in petroleum ether, the remaining whiteprecipitate is filtered off and then the filtrate is evaporated toproduce 3.3 g of the expected compound in the form of a liquid.

NMR CDCl₃ (200 MHz): 1.33 ppm: t: 3H; 4.34 ppm: q: 2H; 6.69-7.38 ppm:unresolved peak: 4H; 12.16 ppm: unresolved peak: 1H.

Preparation 2.3 Ethyl 2-(3,5-dimethylphenyl)-3-hydroxy-2-propenoate(III)

10 ml of ethyl 2-(3,5-dimethylphenyl)acetate are dissolved in 80 ml ofethyl formate. 5 g of 50% NaH are added portionwise and then the mixtureis stirred at AT for 12 hours. The mixture is poured onto a 1N HClsolution and then extraction is carried out with AcOEt. The organicphase is evaporated to produce the expected compound, used as is in thefollowing stage.

Preparation 2.4 Ethyl 2-(4-methoxyphenyl)-3-hydroxy-2-propenoate (III)

8.9 ml of ethyl p-methoxyphenylacetate are dissolved in 80 ml of ethylformate. 4.6 g of 50% NaH are added portionwise and then the mixture isstirred at ambient temperature for 12 hours. It is poured onto a 1N HClsolution and then extraction is carried out with AcOEt. Purification iscarried out by chromatography on a silica column eluted with anAcOEt/heptane (05/95; v/v) mixture to produce 4.0 g of the expectedcompound in the liquid form.

NMR CDCl₃ (200 MHz): 1.30 ppm: t: 3H; 3.83 ppm: s: 3H; 4.29 ppm: q: 2H;6.89-7.21 ppm: unresolved peak: 5H.

Preparation 2.5 Methyl2-[4-(benzyloxy)phenyl]-3-dimethylamino-2-propenoate (IV)

200 μl of tetramethylethylenediamine are added to 5 g of methyl2-[4-(benzyloxy)phenyl]acetate in 5.2 ml ofdimethoxy-N,N-dimethylmethanamine, and the mixture is stirred at 130° C.for three hours. After cooling to AT, ethyl acetate and 60 ml ofammonium chloride are added, the mixture is stirred for five minutes,the organic phase is separated and the aqueous phase is extracted twicewith ethyl acetate. After evaporating the solvent under reduced pressureand then treatment with active charcoal, 4.16 g of the expected compoundare recovered after washing the solid with pentane.

NMR CDCl₃ (200 MHz): 2.66 ppm: s: 3H; 3.62 ppm: s: 3H; 5.45 ppm: s: 2H;6.91 ppm: d: 2H; 7.14 ppm: d: 2H; 7.55 ppm: unresolved peak: 5H; 7.57ppm: s: 1H.

Preparation 2.6 Ethyl 2-(3-bromophenyl)-3-hydroxy-2-propenoate (III) A)Ethyl 3-bromophenylacetate

5 g of 3-bromophenylacetic acid are dissolved in 80 ml of ethanol, 3 mlof concentrated H₂SO₄ are added and then the mixture is heated at refluxfor two hours. The ethanol is evaporated, neutralization is carried outwith a saturated K₂CO₃ solution and then extraction is carried out withAcOEt. The organic phase is dried over MgSO₄. 5.2 g of the expectedcompound are obtained in the liquid form.

NMR CDCl₃ (300 MHz): 1.18 ppm: t: 3H; 3.50 ppm: s: 2H; 4.08 ppm: q: 2H;7.09-7.37 ppm: unresolved peak: 4H.

B) Ethyl 2-(3-bromophenyl)-3-hydroxy-2-propenoate (III)

5.2 g of the compound from the preceding stage are dissolved in 70 ml ofethyl formate, and 1.7 g of 60% NaH are added portionwise. The mixtureis left stirring at AT for five hours. It is poured onto 100 ml of 1NHCl and then extraction is carried out with AcOEt. The organic phase isdried over MgSO₄ and then evaporated to dryness. 5.8 g of the expectedcompound are obtained in the form of an oil.

NMR CDCl₃ (300 MHz): 1.9 ppm: t: 3H; 4.20 ppm: q: 2H; 7.11-7.42 ppm:unresolved peak: 5H; 12.06 ppm: d: 1H.

The intermediaries of formula (III) collated in the table below areobtained by operating according to the Preparations described above:

TABLE 2 (III)

or

Prep- Characterization aration R₃ NMR 2.7 2,4-diCl- CDCl₃(300 MHz): 1.25ppm:t:3H; phenyl 4.25 ppm:q:2H; 7.13-7.44 ppm: unresolved peak:4H; 12.03ppm: unresolved peak:1H. 2.8 3,4-diCl- CDCl₃(300 MHz): 1.29 ppm:t:3H;phenyl 4.31 ppm:q:2H; 7.08-7.42 ppm: unresolved peak:4H; 12.16 ppm:unresolved peak:1H. 2.9 3-CF₃-phenyl CDCl₃(200 MHz): 1.30 ppm:t:3H; 4.31ppm:q:2H; 7.31-7.55 ppm: unresolved peak:4H; 12.19 ppm: unresolvedpeak:1H. 2.10 3,5-CF₃-phenyl CDCl₃(200 MHz): 1.30 ppm:t:3H; 4.36ppm:q:2H; 7.30-7.83 ppm: unresolved peak:4H; 12.32 ppm: unresolvedpeak:1H. 2.11 1,3- CDCl₃(200 MHz): 1.20 ppm:t:3H; benzodioxol-5- 4.33ppm:q:2H; 6 ppm:s:2H; 6.7- yl 6.9 ppm:unresolved peak:3H; 7.29 ppm:d:1H;12.06 ppm:d:1H. 2.12 2,5-diOMe- unpurified phenyl 2.13 3,4-diOMe-CDCl₃(200 MHz): 1.34 ppm:t:3H; phenyl 3.91 and 3.92 ppm:2s:6H; 4.33ppm:q:2H; 6.7-7.0 ppm: unresolved peak:3H; 7.32 ppm:d:1H; 12.07ppm:d:1H. 2.14 3,5-diF-phenyl CDCl₃(200 MHz): 1.33 ppm:t:3H; 4.34ppm:q:2H; 6.69-7.38 ppm: unresolved peak:4H; 12.16 ppm: unresolvedpeak:1H. 2.15 2,4-diF-phenyl CDCl₃(200 MHz): 1.35 ppm:t:3H; 4.24-4.35ppm:q:2H; 6.82- 7.30 ppm:unresolved peak:4H; 12.16 ppm:unresolvedpeak:1H. 2.16 2,3-diF-phenyl CDCl₃(200 MHz): 1.30 ppm:t:3H; 4.30ppm:q:2H; 6.96-7.34 ppm: unresolved peak:4H; 12.24 ppm:d: 1H. 2.173,5-diCl- CDCl₃(200 MHz): 1.26 ppm:t:3H; phenyl 4.29 ppm:q:2H; 7.16-7.49ppm: unresolved peak:4H. 2.18 3-F, 5-CF₃- CDCl₃(200 MHz): 1.32 ppm:t:3H;phenyl 4.31 ppm:q:2H; 7.21-7.40 ppm: unresolved peak:4H; 12.26 ppm:unresolved peak:1H. 2.19 2,4-diF-phenyl CDCl₃(200 MHz): 1.35 ppm:t:3H;4.24-4.35 ppm:q (J = 7.1):2H; 6.82- 7.30 ppm:unresolved peak:4H; 12.16ppm:unresolved peak:1H. 2.20 4-SO₂Me-phenyl Oil 2.21 (4-OMe, 3,5- 1.38ppm:t (J = 7.2):3H; di-tBu)phenyl 1.56 ppm:s:18H; 3.83 ppm:s:3H; 4.41ppm:q (J = 7.2):2H; 7.27-7.44 ppm:unresolved peak:3H; 12.21:d (J =12.7):1H. 2.22 3,4,5,-triOMe- CDCl₃(200 MHz): 1.36 ppm:t phenyl (J =7.1):3H; 3.88, 3.89 and 3.90 ppm:3s:9H; 4.35 ppm:q (J = 7.1):2H; 6.53ppm:s:2H; 7.36 ppm:d (J = 12.7):1H; 12.12 ppm:d (J = 7.1):1H. 2.233,5-diOMe- CDCl₃(300 MHz): 1.32 ppm:t:3H; phenyl 3.80 ppm:s:6H;4.27-4.34 ppm:q (J = 7.2):2H; 6.49 ppm:unresolved peak:3H; 7.34ppm:d:1H; 12.14 ppm:d (J = 12.5):1H 2.24 4-N₃-phenyl d6-DMSO (200 MHz):1.1 ppm:t:3H; 4 ppm:q:2H; 7 ppm:d:2H; 7.3 ppm:d:2H; 7.8 ppm:s:1H; 11ppm:s:1H 2.25 2,4-diOMe- phenyl 2.26 3-N₃-phenyl d₆-DMSO (200 MHz): 1.2ppm:t:3H; 4.1 ppm:q:2H; 7 ppm:s:1H; 7.05 ppm:d:1H; 7.2 ppm:d:1H; 7.35ppm:unresolved peak:2H; 7.9 ppm:s:1H. 2.27 2-Cl, 4-F- CDCl₃ (300 MHz):1.16 ppm:t phenyl (J = 7.2):3H; 4.13 ppm:q (J = 7.2):2H; 6.89-7.90 ppm:unresolved peak:4H; 11.90 ppm:d (J = 12.7):1H

Preparation 2.28 Ethyl2-(6-chloro-1,3-benzodioxol-5-yl)-3-hydroxyacrylate A)5-Bromomethyl-6-chloro-1,3-benzodioxole

2.5 g of 6-chloropiperonyl alcohol are dissolved in 80 ml of ethylether. The solution is cooled to 0° C. and then 1.9 ml of PBr₃ areadded. The mixture is stirred at ambient temperature for 18 hours. It ispoured onto ice and then extraction is carried out with AcOEt. Theorganic phase is washed with a saturated NaCl solution. 3.3 g of powderare obtained.

NMR CDCl₃ (300 MHz): 4.47 ppm: s: 2H; 5.92 ppm: s: 2H; 6.77 ppm: s: 1H;6.88 ppm: s: 1H.

B) (6-Chloro-1,3-benzodioxol-5-yl)acetonitrile

3.3 g of the compound from the preceding stage are dissolved in 70 ml ofethanol and 15 ml of water. 1.8 g of KCN are added and then the mixtureis heated at reflux for 5 hours. The ethanol is evaporated, the residueis taken up in water and then extraction is carried out with AcOEt. Theorganic phase is dried over MgSO₄ and then evaporated to dryness. 2.4 gof oil are obtained.

NMR CDCl₃ (300 MHz): 3.75 ppm: s: 2H; 6.02 ppm: s: 2H; 6.88 ppm: s: 1H;6.95 ppm: s: 1H.

C) Ethyl (6-chloro-1,3-benzodioxol-5-yl)acetate

2.4 g of compound from the preceding stage are dissolved in 80 ml ofethanol and 4 ml of concentrated H₂SO₄. The mixture is heated at refluxfor 48 hours. The ethanol is evaporated, the residue is taken up inwater and then extraction is carried out with AcOEt. The organic phaseis washed with a saturated NaCl solution, dried over MgSO₄ and thenevaporated to dryness. 2.9 g of oil are obtained, which oil comprisesapproximately 20% of starting material.

NMR CDCl₃ (300 MHz): 1.26 ppm: t (J=6.9): 3H; 3.68 ppm: s: 2H; 4.15-4.23ppm: q (J=6.9): 2H; 5.98 ppm: s: 2H; 6.77 ppm: s: 1H; 6.87 ppm: s: 1H.

D) Ethyl 2-(6-chloro-1,3-benzodioxol-5-yl)-3-hydroxyacrylate

2.9 g of compound from the preceding stage are dissolved in 60 ml ofethyl formate. 1.0 g of 60% NaH is added and then the mixture is stirredat ambient temperature for 5 hours. It is poured onto 100 ml of a 1N HClsolution and then extraction is carried out with AcOEt. The organicphase is dried over MgSO₄ and evaporated to dryness. 3.2 g of oil areobtained, which oil is used as is for the continuation.

Preparation 2.29 Ethyl 2-(3-hydroxyphenyl)-3-dimethylaminoacrylate A)Methyl (3-hydroxyphenyl)acetate

10 g of 3-hydroxyphenylacetic acid are dissolved in 60 ml of methanoland 2.5 ml of sulphuric acid. The solution is heated at reflux for twohours. It is brought back to ambient temperature and the methanol isevaporated. The residue is taken up in a saturated K₂CO₃ solution.Extraction is carried out with AcOEt. The organic phase is dried overMgSO₄, filtered and evaporated to dryness. 11.1 g of oil are obtained.

NMR d₆-DMSO (300 MHz): 3.57 ppm: s: 3H; 3.61 ppm: s: 2H; 6.66 ppm:unresolved peak: 3H; 7.09 ppm: unresolved peak: 1H; 9.42 ppm: s: 1H.

B) Ethyl (3-benzyloxyphenyl)acetate

3 g of the compound from the preceding stage are dissolved in 13 ml ofethanol. 3.75 g of K₂CO₃, 3.12 ml of benzyl chloride and a spatula tipof nBu₄NI are added. The mixture is heated at reflux for 6 hours. It isbrought back to ambient temperature, filtration through K₂CO₃ is carriedout and evaporation to dryness is carried out. The residue is taken upin AcOEt and the organic phase is washed with water. 5 g of oil areobtained.

NMR d₆-DMSO (300 MHz): 1.19 ppm: t: 3H; 3.64 ppm: s: 2H; 5.08 ppm: s:2H; 6.85-6.98 ppm: unresolved peak: 2H; 7.22-7.51 ppm: unresolved peak:7H.

C) Ethyl 2-(3-hydroxyphenyl)-3-dimethylaminoacrylate

5 g of the compound from the preceding stage are dissolved in 8 ml ofdimethylformamide dimethyl acetal (DMFDMA). The solution is heated at135° C. for 24 hours while adding 1 ml of DMFDMA every three hoursapproximately. The mixture is evaporated to dryness. 6 g of oil areobtained.

The intermediates of formula (IV) collated in the table below areobtained by operating according to Preparation 2.1:

TABLE 3 (IV)

Prep- Characterization aration R₃ NMR 3.1 4-NMe₂-phenyl 3.2 2,6-diCl-d₆-DMSO (200 MHz): 2.8 ppm:s:6H; phenyl 3.5 ppm:s:3H; 7.3-7.55 ppm:unresolved peak:3H; 7.6 ppm:s:1H. 3.3 3-Br, 4-OMe- 125° C. phenyl 3.42,4-diCl- d₆-DMSO (200 MHz): 2.6 ppm:s:6H; phenyl 3.4 ppm:s:3H; 7.1-7.3ppm: unresolved peak:2H; 7.4-7.5 ppm: unresolved peak:2H. 3.5 2-Br, 4,5-115° C. diOMe-phenyl 3.6 2-Cl, 4,5- d₆-DMSO (200 MHz): 2.6 ppm:s:6H;diOMe-phenyl 3.4 ppm:s:3H; 3.6 ppm:s:3H; 3.65 ppm:s:3H; 6.65 ppm:s:1H;6.85 ppm:s:1H; 7.4 ppm:s:1H. 3.7 3-CN, 4-OMe- 125° C. phenyl 3.82,4-diMe- — phenyl 3.9 3,4-diMe- — phenyl 3.10 4-OBn-phenyl d₆-DMSO/TFA(200 MHz): 2.6 ppm:s:6H; 3.4 ppm:s:3H; 5 ppm:s:2H; 6.8-7 ppm:unresolvedpeak:4H; 7.1-7.25 ppm: unresolved peak:6H. 3.11 4-(OCH₂COOMe)- d₆-DMSO(300 MHz): 2.64 ppm:s:6H; phenyl 3.50 ppm:s:3H; 3.70 ppm:s:3H; 4.75ppm:s:2H; 6.64-7.48 ppm: unresolved peak:4H; 7.95 ppm:s:1H. 3.123,5-diOMe- CDCl₃ (300 MHz): 2.30 ppm:s:6H; phenyl 2.68 ppm:s:6H; 3.64ppm:s:3H; 6.81-6.86 ppm:unresolved peak: 3H; 7.54 ppm:s:1H

Preparation 3.13 Ethyl2-(4-bromo-2-chlorophenyl)-3-dimethylaminoacrylate A)4-Bromo-1-bromomethyl-2-chlorobenzene

5.0 g of 2-chloro-4-bromotoluene are dissolved in 120 ml of CCl₄. 4.3 gof NBS and 1.6 g of AIBN are added. The mixture is heated at reflux for15 hours, water is added, the two phases are separated and thenextraction is carried out with CH₂Cl₂. Purification is carried out bychromatography on a silica column eluted with petroleum ether. 3.8 g ofliquid are obtained.

CDCl₃ (300 MHz): 4.48 ppm: s: 2H; 7.23-7.36 ppm: unresolved peak: 2H;7.51 ppm: s: 1H.

B) (4-Bromo-2-chlorophenyl)acetonitrile

3.8 g of the compound from the preceding stage are dissolved in 70 ml ofethanol and 15 ml of H₂O. 1.7 g of KCN are added and then the mixture isheated at reflux for 5 hours. The ethanol is evaporated, the residue istaken up in water and then extraction is carried out with AcOEt. 2.5 gof oil are obtained.

CDCl₃ (300 MHz): 3.79 ppm: s: 2H; 7.35-7.49 ppm: unresolved peak: 2H;7.59 ppm: s: 1H.

C) Ethyl (4-bromo-2-chlorophenyl)acetate

2.5 g of the compound from the preceding stage are dissolved in 80 ml ofethanol and 4 ml of concentrated H₂SO₄. The solution is heated at refluxfor four days. The ethanol is evaporated, the residue is taken up in asaturated K₂CO₃ solution, and the organic phase is dried over MgSO₄ andthen evaporated to dryness. 2.5 g of liquid are obtained.

CDCl₃ (300 MHz): 1.28 ppm: t (J=7.1): 3H; 3.73 ppm: s: 2H; 4.18 ppm: q(J=7.1): 2H; 7.18 ppm: unresolved peak: 1H; 7.38 ppm: unresolved peak:1H; 7.56 ppm: s: 1H.

D) Ethyl 2-(4-bromo-2-chlorophenyl)-3-dimethylaminoacrylate

2.8 g of the compound from the preceding stage are dissolved in 3.1 g ofBredereck's reagent. The solution is heated at 100° C. for 15 hours andthe excess reagent is evaporated. 2.9 g of oil are obtained.

CDCl₃ (300 MHz): 1.18 ppm: t (J=7.1): 3H; 2.72 ppm: s: 6H; 4.09 ppm: q(J=7.1): 2H; 7.15 ppm: unresolved peak: 1H; 7.35 ppm: unresolved peak:1H; 7.54 ppm: unresolved peak: 1H; 7.60 ppm: s: 1H.

EXAMPLE 1 Compound 63-(3,5-Difluorophenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

25 g of the compound from Preparation 2.1 and 22.5 g of the compoundfrom Preparation 1.1 are mixed in 75 ml of acetic acid and the mixtureis heated at 40° C. for 24 hours and then at 60-65° C. for 4 hours. Thereaction medium is cooled to AT and is then poured onto 275 ml of water.The precipitate formed is recovered, washed with 50 ml of water and thenrecrystallized from 250 ml of MiBK. The residual water is removed byazeotropic distillation at atmospheric pressure. The product obtained iswashed twice with 25 ml of MiBK and then dried at 40-45° C. underreduced pressure for 24 hours to give 20.33 g of the expected compoundafter crystallization from MiBK (20.33 g), M.p.=240° C.

NMR d₆-DMSO (200 MHz): 2.51 ppm: s: 3H; 4.05 ppm: s: 6H; 6.69-8.08 ppm:unresolved peak: 7H.

EXAMPLE 2 Compound 223-(3,5-Difluorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

1.5 g of hydrochloride from Preparation 1.2 are dissolved in 50 ml ofpyridine. 1.9 g of the compound from Preparation 2.2 are added and themixture is heated at 70° C. for 20 hours. The mixture is evaporated todryness and the residue is then taken up in water and extracted withCH₂Cl₂. Purification is carried out by chromatography on a silica columneluted with an AcOEt/heptane (50/50; v/v) mixture to produce 300 mg ofthe expected compound in the form of a powder, M.p.=189° C.(decomposition).

NMR d₆-DMSO (300 MHz): 2.51 ppm: s: 3H; 3.70 ppm: s: 3H; 7.04-8.68 ppm:unresolved peak: 7H; 11.98 ppm: s: 1H.

EXAMPLE 3 Compound 161,6-Dimethyl-3-(3,5-dimethylphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

0.8 g of the compound from Preparation 1.2 is dissolved in 50 ml ofpyridine. 0.8 g of compound from Preparation 2.3 is added and themixture is heated at 80° C. for 20 hours. The mixture is evaporated todryness and then the residue is taken up in water and extracted withCH₂Cl₂. Purification is carried out by chromatography on a silica columneluted with an AcOEt/heptane (50/50; v/v) mixture to produce 500 mg ofthe expected compound, after recrystallization from isopropanol.

NMR d₆-DMSO (200 MHz): 2.23 ppm: s: 6H; 2.49 ppm: s: 3H; 3.73 ppm: s:3H; 6.84-8.08 ppm: unresolved peak: 7H; 9.98 ppm: s: 1H.

EXAMPLE 4 Compound 206-Methoxy-1,9-dimethyl-3-(3,5-difluorophenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

2.5 g of the compound from Preparation 1.3 are dissolved in 70 ml ofpyridine. 3.3 g of the compound from Preparation 2.2 are added and themixture is heated at 100° C. for 20 hours. The mixture is evaporated todryness and then the residue is taken up in water and AcOEt. Theremaining precipitate is filtered off. Recrystallization is carried outfrom isopropanol to produce 1.35 g of the expected compound, M.p.=189°C.

NMR CDCl₃ (200 MHz): 3.91 ppm: s: 3H; 4.04 ppm: s: 6H; 6.68-8.05 ppm:unresolved peak: 7H.

EXAMPLE 5 Compound 13-(3,5-Dimethylphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared from the compounds of Preparations 1.1 and2.3, M.p.=210° C.

NMR CDCl₃ (200 MHz): 2.42 ppm: s: 6H; 2.54 ppm: s: 3H; 4.07 ppm: s: 6H;7.00-8.08 ppm: unresolved peak: 7H.

EXAMPLE 6 Compound 23-(2,4-Dichlorophenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared from the compounds of Preparations 1.1 and2.7, M.p.=170° C.

NMR CDCl₃ (300 MHz): 2.51 ppm: s: 3H; 4.09 ppm: s: 3H; 4.11 ppm: s: 3H;7.15-8.00 ppm: unresolved peak: 7H.

EXAMPLE 7 Compound 213-(2,4-Dichlorophenyl)-6-methoxy-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared from the compounds of Preparations 1.3 and2.7, M.p.=130° C.

NMR CDCl₃ (300 MHz): 3.90 ppm: s: 3H; 4.07 ppm: s: 3H; 4.09 ppm: s: 3H;6.93-7.98 ppm: unresolved peak: 7H.

EXAMPLE 8 Compound 323-(2,4-Dichlorophenyl)-1,5,7,9-tetramethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared from the compounds of Preparations 1.11 and2.7, M.p.=204° C.

NMR CDCl₃ (300 MHz): 2.51 ppm: s: 3H; 2.68 ppm: s: 3H; 4.10 ppm: s: 6H;6.91 ppm: s: 1H; 7.05 ppm: s: 1H; 7.31 ppm: dd: 1H; 7.44 ppm: d: 1H;7.52 ppm: d: 1H; 8.11 ppm: s: 1H.

EXAMPLE 9 Compound 663-(4-Hydroxyphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indoloneA)3-(4-Methoxyphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indolone

2.0 g of hydrochloride obtained in Preparation 1.1 are dissolved in 50ml of pyridine. 2.1 g of formyl ester obtained in Preparation 2.4 areadded and the mixture is heated at 80° C. for 20 hours. The mixture isevaporated to dryness, then extraction is carried out with CH₂Cl₂ andwashing is carried out with water. Purification is carried out bychromatography on a silica column eluted with an AcOEt/heptane/CH₂Cl₂(50/50/50; v/v/v) mixture to produce 0.5 g of the expected compound inthe form of a powder.

NMR d₆-DMSO (200 MHz): 2.50 ppm: s: 3H; 3.86 ppm: s: 3H; 4.05 ppm: s:6H; 6.96-8.04 ppm: unresolved peak: 8H.

B)3-(4-Hydroxyphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indolone

18 ml of BBr₃, in solution in DCM, are added, with stirring and at −78°C., to 5.36 g of the compound from the preceding stage dissolved in 60ml of DCM. The mixture is allowed to return to ambient temperature. Thismixture is subsequently stirred at this temperature for 24 hours. Thereaction medium is diluted with a mixture of DCM and MeOH. The solutionis evaporated under reduced pressure. The crude product is taken up inDCM and adsorbed on 16 g of silica and chromatographed on a silicacolumn with a (97/3; v/v) then (95/5; v/v) up to (50/50; v/v) DCM/MeOHmixture. A solid is thus recovered and suspended in a DCM/MeOH mixture.The suspension obtained is cooled and filtered. The precipitate is thencollected. 4 g of the expected compound are thus recovered, comprising4% of starting compound, M.p.>280° C.

NMR d₆-DMSO (200 MHz): 2.3 ppm: s: 3H; 3.9 ppm: s: 3H; 4 ppm: s: 3H; 6.6ppm: d: 2H; 7 ppm: d: 1H; 7.3 ppm: d: 1H; 7.5 ppm: d: 2H; 7.6 ppm: s:1H; 8.1 ppm: s: 1H.

EXAMPLE 10 Compound 681,6-Dimethyl-3-(4-hydroxyphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indolone A)1,6-Dimethyl-3-(4-benzyloxyphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indolone

1 g of N,5-dimethyl-1H-indole-2-amine (Preparation 1.2) is mixed with1.4 g of the compound from Preparation 2.5 and 10 ml of acetic acid, andthen the mixture is heated at 100° C. for 18 hours. The mixture isevaporated to dryness under vacuum and then the residue is taken up in20 ml of CH₂Cl₂ and 5 ml of H₂O. The pH is brought to 7 with 1N NaOHwith stirring, the two layers are then separated by settling and theorganic phase is washed with NaCl and then dried and evaporated todryness. The residue is taken up in 10 ml of Et₂O, filtration is carriedout and then the organic phase is washed and dried.

B) 1,6-Dimethyl-3-(4-hydroxyphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indolone

0.800 g of the compound from the preceding stage and 50 ml of TFA aremixed. The mixture is heated at 75° C. for 1 hour 30 minutes. Themixture is evaporated to dryness under vacuum and then the residue istaken up in 15 ml of Et₂O and drying is carried out, M.p.=186° C.

NMR d₆-DMSO (300 MHz): 2.6 ppm: s: 3H; 3.8 ppm: s: 3H; 6.8 ppm: d: 2H;7.1 ppm: d: 1H; 7.4 ppm: d: 1H; 7.6 ppm: d: 2H; 7.8 ppm: s: 1H; 8.2 ppm:s: 1H; 11.9 ppm: s: 1H.

EXAMPLE 11 Compound 524-(1,6,9-Trimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-yl)benzonitrileA)3-(3-Bromophenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

2.5 g of the compound from Preparation 1.1 are dissolved in 40 ml ofacetic acid and 60 ml of pyridine; 3.5 g of the compound fromPreparation 2.6 are added and then the mixture is heated at 100° C. for15 hours. The reaction medium is poured into 200 ml of water and theprecipitate formed is filtered off. The latter is taken up in CH₂Cl₂ andthen washed with a saturated NaCl solution, dried over MgSO₄ andevaporated to dryness. The precipitate is taken up in anAcOEt/cyclohexane (20/8; v/v) mixture and is then filtered. 20 g of theexpected compound are obtained, M.p.=215-216° C.

B)4-(1,6,9-Trimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-yl)benzonitrile

3 g of the compound obtained in the preceding stage are dissolved in 50ml of 1-methyl-2-pyrrolidinone, 1.4 g of CuCN are added and then themixture is heated at 200° C. for 4 hours. The reaction medium is pouredonto 100 ml of CH₂Cl₂ and then the precipitate formed is filtered off.The filtrate is washed with a 1N HCl solution and is then dried overMgSO₄. The product obtained is purified by chromatography on silica,elution being carried out with AcOEt/CH₂Cl₂ (50/50; v/v) and thenAcOEt/MeOH/NH₃ (90/10/1; v/v/v). 2.2 g of the expected compound arecollected in the form of a powder.

NMR CDCl₃ (300 MHz): 2.52 ppm: s: 3H; 4.09 ppm: s: 3H; 4.12 ppm: s: 3H;7.16 ppm: unresolved peak: 8H.

EXAMPLE 12 Compound 533-(4-(Aminomethyl)phenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

50 mg of sodium hydroxide are dissolved in 11 ml of ethanol, 0.2 g ofthe compound obtained in the preceding example are added, followed byapproximately 100 mg of Raney Ni, and the mixture is hydrogenated for 24hours under 50 psi. The catalyst is filtered off through Celite®,rinsing is then carried out with methanol and evaporation is carried outto dryness. The residue is taken up in a 1N HCl solution and then theimpurities are extracted with AcOEt. The solution is basified to pH=9with a K₂CO₃ solution and then extraction is carried out with AcOEt toproduce 90 mg of the expected compound in the form of a powder.

NMR CDCl₃ (300 MHz): 2.51 ppm: s: 3H; 3.91 ppm: s: 2H; 4.08 ppm: s: 6H;7.13-8.09 ppm: unresolved peak: 8H.

EXAMPLE 13 Compound 84 Methyl(3-(2,4-dichlorophenyl)-1,6-dimethyl-2-oxo-1,2-dihydro-9H-pyrido[2,3-b]indol-9-yl)acetate

1 g of 3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro[2,3-b]indol-2-one(compound 46) is dissolved in 10 ml of DMF, 0.143 g of 95% NaH is addedand, after stirring for 30 minutes, 0.4 ml of methyl bromoacetate isadded. After stirring for one hour at AT, the reaction mixture isevaporated and then the residue is taken up in CH₂Cl₂ and washed with aNaHCO₃ solution and then a NaCl solution. The organic phase is dried andthen evaporated to produce 0.98 g of the expected product.

EXAMPLE 14 Compound 852-(3-(2,4-Dichlorophenyl)-1,6-dimethyl-2-oxo-1,2-dihydro-9H-pyrido[2,3-b]indol-9-yl)-N-methylacetamide

0.3 g of the ester obtained in the preceding example and 30 ml of 33%methylamine in EtOH are mixed. After stirring at AT for 5 hours, thereaction medium is evaporated and the residue is taken up in Et₂O andthen filtration and drying are carried out to produce 0.260 g of theexpected compound.

EXAMPLE 15 Compound 813-(3-Hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA)3-(1,6-Dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]-indol-3-yl)benzaldehyde

450 mg of3-(3-cyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one,10 ml of AcOH, 20 ml of pyridine, 2.6 g of sodium hypophosphite and 434mg of Raney Ni are mixed and then the mixture is heated at 60° C. for 4hours. The reaction medium is filtered and the filtrate is evaporated;the residue is taken up in 50 ml of AcOEt/CH₂Cl₂ (1/1; v/v) and theorganic phase is washed with water, dried and evaporated to produce theexpected compound, M.p.=280° C.

B)3-(3-Hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

280 mg of the compound obtained in Stage A are placed in 10 ml of CH₂Cl₂and the minimum amount of AcOH to dissolve the compound, 375 mg ofNaBH(OAc)₃ are added and then the mixture is left stirring at AT for 18hours. The reaction medium is evaporated and the residue is taken up inAcOEt and then filtration is carried out to produce 200 mg of theexpected compound.

EXAMPLE 16 Compound 801,6-Dimethyl-3-(3-((methylamino)methyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

280 mg of the compound from Stage A of the preceding example are placedin 10 ml of CH₂Cl₂ and the minimum amount of AcOH to dissolve thecompound and then 375 mg of NaBH(OAc)₃ and 0.064 ml of methylamine areadded. After stirring at AT for 18 hours, extraction is carried outthree times with 10 ml of water and then the aqueous phase is extractedwith AcOEt. After evaporating, 15 mg of the expected compound areobtained.

EXAMPLE 17 Compound 833-(1,6-Dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-yl)benzaldehydeoxime

210 mg of the compound from Example 15, Stage A, are dissolved in 5 mlof MeOH, 46 mg of hydroxylamine hydrochloride, in solution in theminimum amount of water, are added and the mixture is left stirring atAT for two hours. The mixture is evaporated to dryness and then theresidue is chromatographed on silica, elution being carried out withAcOEt/CH₂Cl₂ (2/8; v/v). 74 mg of the expected compound are obtained.

EXAMPLE 18 Compound 1101,6-Dimethyl-3-(3-methoxycarbonylphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA)3-(3-Bromophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared according to the usual methods by reaction ofN,1,5-trimethyl-1H-indole-2-amine with ethyl2-(3-bromophenyl)-3-hydroxy-2-propenoate.

NMR d₆-DMSO (200 MHz): 2.42 ppm: s: 3H; 3.69 ppm: s: 3H; 7.04 ppm: d:1H; 7.35 ppm: d: 1H; 7.05-7.08 ppm: unresolved peak: 5H; 8.30 ppm: s:1H; 11.91 ppm: s: 1H.

B)1,6-Dimethyl-3-(3-methoxycarbonylphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

500 mg of the compound from the preceding stage and 140 mg of1,3-bis(diphenylphosphino)propane are dissolved in 20 ml of anhydrousMeOH. 1.9 ml of 99.9% triethylamine, 15 ml of anhydrous DMSO and then 60mg of Pd(OAc)₂ are added. CO is bubbled into the reaction medium for 20minutes and the medium is heated at 75° C. overnight under a COatmosphere. The medium is allowed to return to ambient temperature. Thereaction medium is poured onto 200 ml of water and is then extractedwith AcOEt. The organic phase is dried over MgSO₄, filtered andevaporated to dryness. The residue is purified on a silica column elutedwith an AcOEt/petroleum ether (v/v; 75/25) mixture. The precipitateobtained is triturated with an AcOEt/petroleum ether mixture. 260 mg ofa powder are obtained.

NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.70 ppm: s: 3H; 3.88 ppm: s:3H; 7.05 ppm: unresolved peak: 1H; 7.35 ppm: d (J=8): 1H; 7.54 ppm:unresolved peak: 1H; 7.74 ppm: unresolved peak: 1H; 7.86 ppm: unresolvedpeak: 1H; 8.02 ppm: unresolved peak: 1H; 8.43 ppm: unresolved peak: 1H;11.94 ppm: s: 1H.

EXAMPLE 19 Compound 1113-(4-Aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA)3-(4-Bromophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

This compound is prepared according to the usual methods by reaction ofN,1,5-trimethyl-1H-indole-2-amine with ethyl2-(4-bromophenyl)-3-hydroxy-2-propenoate.

NMR d₆-DMSO (300 MHz): 2.35 ppm: s: 3H; 3.61 ppm: s: 3H; 3.97 ppm: d:1H; 7.03 ppm: d: 1H; 7.45-7.80 ppm: unresolved peak: 5H; 8.32 ppm: s:1H; 11.85 ppm: s: 1H.

B)3-(4-Aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

10 ml of THF are degassed for 10 minutes and 9.2 mg of Pd₂(dba)₃, then370 mg of the compound from the preceding stage, then 9.4 mg of ligand2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and, finally, 2.2ml of a 1M solution of LiN(TMS)₂ in THF are added under argon. Themixture is stirred in a sealed tube at 90° C. for 20 hours. The reactionmedium is cooled, then 10 ml of a 1N HCl solution are added and then themixture is stirred at ambient temperature for 10 minutes. The two phasesare separated and the aqueous phase is washed with AcOEt and thenbasified with a saturated K₂CO₃ solution. The precipitate formed isfiltered off. 90 mg are obtained.

NMR d₆-DMSO (300 MHz): 2.40 ppm: s: 3H; 3.65 ppm: s: 3H; 4.99 ppm: s:2H; 6.57 ppm: unresolved peak: 2H; 6.94 ppm: d (J=8.1): 1H; 7.29 ppm: d(J=8.1): 1H; 7.43 ppm: unresolved peak: 2H; 7.60 ppm: s: 1H; 8.07 ppm:1H.

EXAMPLE 20 Compound 1211,6-Dimethyl-1,9-dihydro-3-(phenylaminophenyl)-2H-pyrido[2,3-b]indol-2-one

13 mg of Pd₂(dba)₃, 500 mg of the compound from Example 18, Stage A, 11mg of ligand 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 3ml of a 1M solution of LiN(TMS)₂ in THF, 127 mg of aniline and then 10ml of anhydrous dioxane are placed under argon. The mixture is stirredin a sealed tube at 65° C. for 24 hours. The mixture is brought back toambient temperature and then AcOEt is added. The organic phase is washedwith a saturated NaCl solution. Purification is carried out on a silicacolumn eluted with an AcOEt/petroleum ether (v/v; 50/50) then (v/v;75/25) mixture. The precipitate obtained is triturated in ether. 55 mgof the expected compound are obtained in the form of a precipitate,M.p.=188-190° C.

NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.68 ppm: s: 3H; 6.77-8.28 ppm:unresolved peak: 14H; 12.00 ppm: s: 1H.

EXAMPLE 21 Compound 1473-(2,4-Dicyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

0.6 g of3-(2-chloro-4-bromophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneis dissolved in 15 ml of NMP. 0.27 g of CuCN is added and then themixture is heated at reflux for 5 hours. The reaction medium is pouredonto CH₂Cl₂ and washing is carried out with a saturated NaCl solution.Purification is carried out by chromatography on a silica column elutedwith an AcOEt/petroleum ether (v/v; 75/25) mixture and then pure AcOEt.The fractions recovered are washed with a 1N HCl solution to remove anNMP residue. 50 mg of the expected compound are obtained in the form ofa powder.

NMR d₆-DMSO (300 MHz): 2.27 ppm: s: 3H; 3.70 ppm: s: 3H; 7.08 ppm: d(J=8.1): 1H; 7.38 ppm: d (J=8.1): 1H; 7.67 ppm: s: 1H; 7.85 ppm: d(J=8.2): 1H; 8.15 ppm: d (J=8.2): 1H; 8.45 ppm: unresolved peak: 2H;12.11 ppm: s: 1H.

EXAMPLE 22 Compound 1433-(3-Acetylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

400 mg of Compound 60 are dissolved in 20 ml of anhydrous THF. Thereaction medium is cooled to 0° C. and then 9.1 ml of 1.4M CH₃Li in THFare added portionwise. The mixture is allowed to return to ambienttemperature and is then stirred for 2 hours. The reaction medium ispoured onto 1N HCl and washing is then carried out with AcOEt. Theaqueous phase is basified with 5N NaOH and then the product is extractedwith AcOEt. The organic phase is dried over MgSO₄, filtered andevaporated to dryness. The residue is purified on a silica column elutedwith an AcOEt/petroleum ether (v/v; 80/20) mixture and then with pureAcOEt. 40 mg of the expected compound are obtained, M.p.=258-260° C.

NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 2.63 ppm: s: 3H; 3.70 ppm: s:3H; 7.03-8.43 ppm: unresolved peak: 8H; 11.92 ppm: s: 1H.

EXAMPLE 23 Compound 1271,6-Dimethyl-3-(3-(pyridin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

500 mg of the compound from Example 18, Stage A, 180 mg of2-aminopyridine, 315 mg of NaOtBu, 50 mg of Pd₂(dba)₃ and 95 mg of Xantphos are dissolved in 7 ml of dioxane (in a sealed tube). The reactionmedium is degassed for 30 minutes and is then heated at 100° C.overnight. It is brought back to ambient temperature. After purifying ona silica column eluted with ethyl acetate, 380 mg of powder areobtained. M.p.=250-252° C.

NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.70 ppm: s: 3H; 6.71-8.27 ppm:unresolved peak: 12H; 9 ppm: s: 1H; 11.88 ppm: s: 1H.

EXAMPLE 24 Compound 94[4-(1,6,9-trimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-yl)phenoxy]acetonitrile

0.1 g of Compound 66 (Example 9) is dissolved in 10 ml of DMF. 90 ml ofK₂CO₃ and then 0.12 ml of bromoacetonitrile are added. The mixture isheated at 90° C. for 48 hours. The reaction medium is poured onto asaturated NH₄Cl solution, the mixture is basified with sodium hydroxideand then extraction is carried out with AcOEt. Purification is carriedout by chromatography on a silica column eluted with an AcOEt/petroleumether (v/v; 75/25) mixture. 20 mg of powder are obtained. M.p.=195-196°C.

NMR d₆-DMSO (300 MHz): 2.73 ppm: s: 3H; 4.27 ppm: s: 6H; 5.02 ppm: s:2H; 7.09-8.26 ppm: unresolved peak: 8H.

EXAMPLE 25 Compound 1331,6-Dimethyl-3-(3-(morpholin-4-ylcarbonyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA) 3-(1,6-Dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-yl)benzoicacid

200 mg of the compound from Example 18 are dissolved in 10 ml of MeOH. 2ml of water and then 97 mg of LiOH.H₂O are added. The mixture is heatedat 80° C. for 20 hours. It is allowed to return to ambient temperature.The MeOH is evaporated, the residue is taken up in water and then theaqueous phase is washed with AcOEt. The aqueous phase is basified with5N NaOH and then extracted with AcOEt. The organic phase is dried overMgSO₄, filtered and evaporated to dryness. The precipitate obtained istriturated with a petroleum ether/AcOEt (2%) mixture. The precipitate isfiltered off and dried. 40 mg of a powder are obtained.

NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.70 ppm: s: 3H; 7.04-8.42 ppm:unresolved peak: 8H; 11.93 ppm: s: 1H; 12.87 ppm: unresolved peak: 1H.

B)1,6-Dimethyl-3-(3-(morpholin-4-ylcarbonyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

200 mg of the compound from the preceding stage are dissolved in 20 mlof CH₂Cl₂. 0.06 ml of morpholine, 340 mg of BOP and 10 ml of DMF areadded. The reaction mixture is stirred at ambient temperature forapproximately 2 hours. The reaction medium is poured onto saturatedNH₄Cl and extracted with AcOEt. Acid/base washing is carried out andthen the precipitate obtained is washed with an iPrOH/petroleum ether(v/v; 50/50) mixture. 90 mg of powder are obtained. M.p.=296-298° C.

NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.38-3.62 ppm: 8H; 3.69 ppm: s:3H; 7.03-8.42 ppm: unresolved peak: 8H; 11.92 ppm s: 1H.

EXAMPLE 26 Compound 1236-Cyano-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA)6-Bromo-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-1H-pyrido[2,3-b]indol-2-one

This compound is prepared by the usual methods.

NMR d₆-DMSO (300 MHz): 2.31 ppm: s: 6H; 3.69 ppm: s: 3H; 6.91 ppm: s:1H; 7.28-7.44 ppm: unresolved peak: 4H; 8.15 ppm: d: 1H; 8.38 ppm: s:1H; 12.30 ppm: s: 1H.

B)6-Cyano-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

2.0 g of the compound from the preceding stage are dissolved in 50 ml ofN-methylpyrrolidinone. 0.9 g of CuCN is added and then the mixture isheated at 200° C. for 24 hours. The reaction medium is poured ontoCH₂Cl₂ and then washing is carried out with a 1N HCl solution. Theproduct is adsorbed on silica and purified by chromatography on a columneluted with an AcOEt/petroleum ether (v/v; 50/50) mixture, then pureAcOEt and then AcOEt/MeOH 2%. 1.2 g of powder are obtained.

NMR d₆-DMSO (300 MHz): 2.31 ppm: s: 6H; 3.70 ppm: s: 3H; 6.93 ppm: s:1H; 7.33 pppm: s: 2H; 7.58 ppm: unresolved peak: 2H; 8.42 ppm:unresolved peak: 2H; 12.55 ppm: s: 1H.

EXAMPLE 27 Compound 96(3-(2,4-Dichlorophenyl)-1,6-dimethyl-2-oxo-1,2-dihydro-9H-pyrido[2,3-b]indol-9-yl)acetonitrile

600 mg of Compound 46 are dissolved in 10 ml of DMF. 42 mg of 95% NaHare added. The mixture is stirred at AT for 30 minutes and then 230 mgof bromoacetonitrile are added. The mixture is stirred at AT for 18hours. It is concentrated by half and precipitation is carried out byaddition of water. 200 mg of the expected product are obtained,M.p.=270° C.

EXAMPLE 28 Compound 929-(3-Aminopropyl)-3-(2,4-dichlorophenyl)-1,6-dimethyl-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]-indol-2-onehydrochloride A)2-(3-(3-(2,4-Dichlorophenyl)-1,6-dimethyl-2-oxo-1,2-dihydro-9H-pyrido[2,3-b]indol-9-yl)propyl)-1H-isoindole-1,3(2H)-dione

0.5 g of Compound 46 is dissolved in 5 ml of DMF, 107 mg of 95% NaH areadded and the mixture is stirred at AT for 10 minutes. 1.25 g of2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione are added and the mixtureis stirred at AT for 18 hours. The mixture is evaporated, the residue istaken up in CH₂Cl₂ and the organic phase is washed with NaCl and thenH₂O. Chromatography is carried out on silica, elution being carried outwith CHCl₃/MeOH (v/v; 98/2). 160 mg of the expected product areobtained, M.p.=249° C.

B)9-(3-Aminopropyl)-3-(2,4-dichlorophenyl)-1,6-dimethyl-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]-indol-2-onechlorohydride

180 mg of the compound from the preceding stage, 3.2 ml of THF, 5 ml ofEtOH and 33 μl of hydrazine hydrate are mixed. The mixture is heated atreflux for 18 hours; filtration is carried out and the HCl phase isevaporated. Drying is carried out. 16 mg of the expected product areobtained, M.p.=198° C.

EXAMPLE 29 Compound 913-(2,4-Dichlorophenyl)-9-(2-hydroxyethyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-oneA)3-(2,4-Dichlorophenyl)-1,6-dimethyl-9-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

695 mg of Compound 46 are dissolved in 7 ml of DMF. 99 mg of 95% NaH areadded. The mixture is stirred at AT for 15 minutes. 813 mg of2-(2-bromoethoxy)tetrahydro-2H-pyran are added and the mixture isstirred at AT for 18 hours. It is evaporated to dryness, the residue istaken up in CH₂Cl₂ and the organic phase is washed with NaCl and thenH₂O. It is dried and evaporated. The residue is chromatographed withCHCl₃/MeOH (v/v; 98/2). 390 mg of the expected product are obtained,M.p.=161° C.

B)3-(2,4-Dichlorophenyl)-9-(2-hydroxyethyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

295 mg of the product from the preceding stage, 1.21 mg ofp-toluenesulphonic acid and 10 ml of 95% EtOH are mixed. The mixture isheated at reflux for 8 hours and evaporated to dryness. The solid iswashed with NaHCO₃ and then H₂O, and dried. 198 mg of the expectedproduct are obtained, M.p.=240° C.

EXAMPLE 30 Compound 1023-(2,4-Dimethylphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

400 mg of3-(2,4-dimethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one(compound 101) are dissolved in 10 ml of DMF. 31 mg of 95% NaH are addedand the mixture is stirred at AT for 30 minutes. 380 μl of methyl iodideare added and the mixture is stirred at AT for 18 hours. It isevaporated to dryness. The residue is taken up in CH₂Cl₂ and the organicphase is washed with NaCl and then water, dried and evaporated. Theresidue is taken up in Et₂O, filtration is carried out and drying iscarried out. 300 mg of the expected product are obtained, M.p.=150° C.

EXAMPLE 31 Compound 573-(2-Chloro-4-methoxyphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one

A mixture of 10 ml of anhydrous DMF and 0.6 ml of anhydrous methanol isprepared and 0.5 g of 60% NaH is added thereto. After gas evolution hasceased, 0.43 g of Compound 59 is added and then the mixture is heated at80° C. for 24 hours. The reaction medium is poured onto a saturatedNH₄Cl solution and then the precipitate formed is filtered off andwashed with an isopropanol/petroleum ether (v/v; 50/50) mixture. 0.35 gof the expected compound is obtained.

NMR d₆-DMSO (300 MHz): 2.46 ppm: s: 3H; 3.72 ppm: s: 3H; 3.87 ppm: s:3H; 6.98-7.15 ppm: unresolved peak: 3H; 7.3-7.6 ppm: unresolved peak:2H; 7.68 ppm: s: 1H; 8.15 ppm: s: 1H; 11.95 ppm: s: 1H.

The chemical structures and the physical properties of a few compoundsaccording to the invention are illustrated in the following table. Inthis table, Me represents methyl, Et represents ethyl, tBu representstert-butyl and Bn represents benzyl.

TABLE 4 (I)

Characterization Compound R₁ R₂ R₃ R₄, R₅ M.p. (° C.) or NMR 1 Me Me3,5-diMe-phenyl 6-Me 210° C. 2 Me Me 2,4-diCl-phenyl 6-Me 170° C. 3 MeMe 3,4-diCl-phenyl 6-Me 230° C. 4 Me Me 3-CF₃-phenyl 6-Me 186° C. 5 MeMe 3,5-diCF₃-phenyl 6-Me 248° C. 6 Me Me 3,5-diF-phenyl 6-Me 240° C. 7Me Me 3,4,5-triOMe-phenyl 6-OMe 224° C. (dec.) 8 Me Me1,3-benzodioxol-5-yl 6-OMe 197° C. 9 Me Me 2,5-diOMe-phenyl 6-Me 225° C.10 Me Me 3,5-diMe-phenyl 6-Cl 200° C. 11 Me Me 1,3-benzodioxol-5-yl7-OMe 220° C. (dec.) 12 Me Me 3,4-diOMe-phenyl 7-OMe 190° C. 13 Me Me3,4,5-triOMe-phenyl 8-OMe 219° C. 14 Me Me 3,4-diOMe-phenyl 6-Me 190° C.15 Me Me 3,5-diOMe-phenyl 6-Me 205° C. 16 H Me 3,5-diMe-phenyl 6-Me NMR17 Me Me 3,5-diOMe-phenyl 6-Cl 229 18 Me Me 3,5-diF-phenyl H 232° C. 19Me Me 2,4-diF-phenyl 6-Me 167° C. 20 Me Me 3,5-diF-phenyl 6-OMe 189° C.21 Me Me 2,4-diCl-phenyl 6-OMe 130° C. 22 H Me 3,5-diF-phenyl 6-Me 189°C. (dec.) 23 Me Me 3,5-diMe-phenyl 6-OMe 194° C. 24 Me Me 3-F,5-CF₃-phenyl 6-Me 190° C. 25 Me Me 3,5-diF-phenyl 5-OMe 238° C. 26 Me Me1,3-benzodioxol-5-yl 8-OMe 197° C. 27 Me Me 3,5-diF-phenyl 7-OH 195° C.28 Me Me 2,4-diCl-phenyl H 241° C. 29 Me Me 2,4-diCl-phenyl 7-OMe NMR 30Me Me 2,4-diCl-phenyl 5-OMe 228° C. 31 Me Me 2,4-diCl-phenyl 7-Cl NMR 32Me Me 2,4-diCl-phenyl 5,7-diMe 240° C. 33 Me Me 2,4-diCl-phenyl 6-Cl258° C. 34 Me Me 3,5-diF-phenyl 6-Cl 295° C. 35 H Me 3,5-diF-phenyl H262° C. 36 H Me 2,4-diCl-phenyl H NMR 37 Me Me 3,5-diMe-phenyl

NMR 38 Me Me 3,5-diCl-phenyl 6-Me 268° C. 39 Me Me 2,3-diF-phenyl 6-Me170° C. 40 Me Me 2,3-diF-phenyl 6-OMe 179° C. 41 H Me 3-CF₃, 5-F-phenyl6-Me 270° C. 42 Me Me 3-OH-phenyl 6-Me NMR 43 Me Me 2-Cl, 4-F-phenyl6-Me 202-203° C. 44 Me Me 4-SO₂Me-phenyl 6-Me 245-246° C. 45 Me Me 2-Cl,4-OMe-phenyl 6-Me 196-197° C. 46 H Me 2,4-diCl-phenyl 6-Me NMR 47 Me Me4-OH, 3-tBu-phenyl 6-Me NMR 48 Me Me

6-Me 194° C. 49 Me Me

6-Me 252° C. 50 Me Me 3-CH₂NH₂-phenyl 6-Me NMR 51 Me Me 3-CONH₂-phenyl6-Me 269° C. 52 Me Me 3-CN-phenyl 6-Me 241-242° C. 53 Me Me4-(CH₂NH₂)-phenyl 6-Me 213-214° C. 54 H Me 4-SO₂Me-phenyl 6-Me 278° C.55 H Me 3,4,5-triOMe-phenyl 6-Me NMR 56 H Me 4-(CH₂NH₂)-phenyl 6-Me 258°C. 57 H Me 2-Cl, 4-OMe-phenyl 6-Me NMR 58 H Me 4-CN-phenyl 6-Me NMR 59 HMe 2-Cl, 4-F-phenyl 6-Me NMR 60 H Me 3-CN-phenyl 6-Me 295° C. 61 H Me3-(CH₂NH₂)-phenyl 6-Me NMR 62 H Me 4-COOMe-phenyl 6-Me NMR 63 H Me 2-Cl,4-OH-phenyl 6-Me NMR 64 H Me 3-NH₂-phenyl 6-Me NMR 65 H Me 4-COOH-phenyl6-Me NMR 66 Me Me 4-OH-phenyl 6-Me 280° C. 67 Me Me 4-NMe₂-phenyl 6-Me118° C. 68 H Me 4-OH-phenyl 6-Me 186° C. 69 Me Me 2,6-diCl-phenyl 6-Me255° C. 70 Me Me 4-[CONH(CH₂)₂N(CH₃)₂]- 6-Me 105° C. phenyl 71 Me Me

6-Me 174° C. 72 Me Me 3-COOMe-phenyl 6-Me 172-173° C. 73 Me Me 2-Cl,4-OH-phenyl 6-Me NMR 74 Me Me 2,4-diCl-phenyl 6-CO₂Me 270° C. 75 H Me4-SMe-phenyl 6-Me 280° C. 76 H Me 4-N(CH₃)₂-phenyl 6-Me 280° C. 77 H Me3,4-diOMe-phenyl 6-Me NMR 78 CH₂—COO-tBu Me 2,4-diCl-phenyl 6-Me 113° C.79 Me Me 2,4-diCl-phenyl 6-CN 290° C. 80 H Me 3-CH₂NH(CH₃)-phenyl 6-MeNMR 81 H Me 3-CH₂OH-phenyl 6-Me NMR 82 H Me 3-Br, 4-OMe-phenyl 6-Me NMR83 H Me 3-(CH═NOH)-phenyl 6-Me 290° C. 84 CH₂—COO—Me Me 2,4-diCl-phenyl6-Me 249° C. 85 CH₂—CONH—Me Me 2,4-diCl-phenyl 6-Me NMR 86 Me Me2,4-diCl-phenyl 6-phenyl 110° C. 87 H Me 2-Br, 4,5-diOMe-phenyl 6-Me NMR88 Me Me 3-CN-phenyl 6-CN >280° C. NMR 89 Me Me 2-Cl, 3,4-diOMe-phenylMe 250° C. 90

Me 2,4-diCl-phenyl 6-Me 161° C. 91 CH₂CH₂—OH Me 2,4-diCl-phenyl 6-Me240° C. 92 (CH₂)₃—NH₂ Me 2,4-diCl-phenyl 6-Me 198° C. hydrochloride 93Me Me 2-Br, 4,5-diOMe-phenyl 6-Me 236° C. 94 Me Me 4-(—OCH₂CN)-phenyl6-Me 192° C. NMR 95 Me Me 4-(OCH₂CH₂NH₂)-phenyl 6-Me 170° C. 96 CH₂CN Me2,4-diCl-phenyl 6-Me 277° C. 97 CH₂CH₂—NH₂ Me 2,4-diCl-phenyl 6-Me NMR98 H Me 2-Cl, 4,5-diOMe-phenyl 6-Me NMR 99 Me Me 2-Cl, 4,5-diOMe-phenyl6-Me 245° C. NMR 100 H Me 4-OMe, 3-CN-phenyl 6-Me NMR 101 H Me2,4-diMe-phenyl 6-Me NMR 102 Me Me 2,4-diMe-phenyl 6-Me 150° C. 103 H Me3,4-diMe-phenyl 6-Me NMR 104 Me Me 3,4-diMe-phenyl 6-Me 211° C. 105 MeMe 4-N₃-phenyl 6-Me 184° C. 106 Me Me 3,4-diOMe-phenyl 6-OMe 160° C. 107Me Me

6-Me 180° C. hydrochloride 108 Me Me 2,3-diF-phenyl 6-OMe 179° C. 109 MeMe 3-tBu, 4-OMe-phenyl 6-Me 231-232° C. 110 H Me 3-COOMe-phenyl 6-Me278-279° C. 111 H Me 4-NH₂-phenyl 6-Me NMR 112 H Me

6-Me 226° C. 113 H Me

6-Me NMR 114 H Me 2,4-diCl-phenyl 6-Br 386° C. (dec.) NMR 115 H Me

6-Me 267-268° C. 116 H Me 6-Cl-1,3-benzodioxol-5-yl 6-Me NMR 117 H Me3,5-diOMe-phenyl 6-Me 299° C. NMR 118 H Me 3-(—NH—CH₂CH₂—NMe₂)-phenyl6-Me 237-239° C. 119 H Me 4-N₃-phenyl 6-Me NMR 120 H Me 2,4-diOMe-phenyl6-Me 308-310° C. 121 H Me 3-(NH—C₆H₅)-phenyl 6-Me 188-190° C. 122 H Me3,5-diMe-phenyl 6-CH₂NH₂ NMR 123 H Me 3,5-diMe-phenyl 6-CN NMR 124 Me Me4-NH₂-phenyl 6-Me 224° C. NMR 125 H Me 3,5-diMe-phenyl 6-Br 320° C.(dec.) NMR 126 H Me 3-CF₃-phenyl 6-Me 246° C. NMR 127 H Me

6-Me 250° C. 128 H Me 2,4-diCl-phenyl 6-OMe 318° C. NMR 129 H Me3-(—OCH₂C₆H₅)-phenyl 6-Me 221° C. NMR 130 H Me 3-OH-phenyl 6-Me 310° C.(dec.) NMR 131 H Me 3,5-diCl-phenyl 6-Me 300-302° C. NMR 132 H Me3,5-diMe-phenyl 6-OMe 317° C. (dec.) 133 H Me

6-Me 296-298° C. 134 H Me 4-CONH₂-phenyl 6-Me NMR 135 Me Me 3-NH₂-phenyl6-Me 133-135° C. 136 H Me 3,5-diMe-phenyl 6-CH₂NMe₂ 238-240° C. 137 H Me3-(—OCH₂COOMe)-phenyl 6-Me 208-209° C. 138 Me Me 4-(—OMe)-phenyl 6-Me80° C. (dec.) NMR 139 H Me

6-Me 190° C. (dec.) 140 H Me

6-Me 316° C. (dec.) NMR 141 CH₂CN Me 3-(OCH₂CN)-phenyl 6-Me 225-227° C.142 (CH₂)₂N—(CH₂)₂ Me 3-OH-phenyl 6-Me 216-218° C. 143 H Me4-(—COMe)phenyl 6-Me 258-260° C. 144 Me Me 3-Br, 4-OMe-phenyl 6-Me245-247° C. 145 H Me 3-N₃-phenyl 6-Me NMR 146 Me Me 3-N₃-phenyl 6-Me188° C. 147 H Me 2,4-diCN-phenyl 6-Me NMR 148 H Me 2-Cl, 4-Br-phenyl6-Me NMR 149 Me Me 2-Cl, 4-Br-phenyl 6-Me 251° C. 150 R₁ + R₂ = —(CH₂)₃—2,4-diCl-phenyl 6-Me 197-198° C. NMR 151 Me Me 2,4-diCN-phenyl 6-Me 292°C. 152 H Me

6-Me 291° C. 153 Me Me 2,4-diCl-phenyl 6-Br 228° C. 154

Me 2,4-diCl-phenyl 6-Br 179-180° C. (dec.) 155 CH₂CN Me 2,4-diCl-phenyl6-COOEt NMR 156 H Me 2,4-diCl-phenyl 6-COOEt NMR 157

Me 2,4-diCl-phenyl 6-Br 210° C. 158 H Me

6-Me 250° C. (dec.) 159 H Me

6-Me NMR 160 H Me

6-Me NMR 161 Me Me

6-Me 262-264° C. 162 H Me 2,4-diCl-phenyl 6-COOMe 322-324° C. 163 H Me2,4-diCl-phenyl 6-SO₂Me 338-340° C. 164 Me Me 2,4-diCl-phenyl 6-SO₂Me156-160° C. 165 H Me 2,4-diOMe-phenyl 6-Br 207-208° C. 166 H Me3,5-diCl-phenyl 6-COOMe NMR 167 H Me 2-Cl, 4-Br-phenyl 6-COOMe 321-323°C. 168 H Me

6-COOMe 297-298° C. 169 H Me 2,4-diOMe-phenyl 6-CN 239-242° C.

Compound 16: NMR d₆-DMSO (300 MHz): 2.3 ppm: s: 6H; 2.4 ppm: s: 3H; 3.67ppm: s: 3H; 6.9 ppm: s: 1H; 7 ppm: d: 1H; 7.3 ppm: unresolved peak: 3H;7.7 ppm: s: 1H; 8.26 ppm: s: 1H; 11.9 ppm: s: 1H.

Compound 29: NMR CDCl₃ (300 MHz): 3.93 ppm: s: 3H; 4.09 ppm: s: 6H; 6.89ppm: d: 1H; 6.92 ppm: dd: 1H; 7.3 ppm: dd: 1H; 7.38 ppm: d: 1H; 7.51ppm: d: 1H; 7.62 ppm: d: 1H; 7.94 ppm: s: 1H.

Compound 31: NMR d₆-DMSO (300 MHz): 4 ppm: s: 3H; 4.15 ppm: s: 3H; 7.23ppm: dd: 1H; 7.42 ppm: d: 1H; 7.47 ppm: dd: 1H; 7.68 ppm: d: 1H; 7.78ppm: d: 1H; 7.88 ppm: d: 1H; 8.23 ppm: s: 1H.

Compound 36: NMR CDCl₃ (300 MHz): 3.83 ppm: s: 3H; 7.29-7.49 ppm:unresolved peak: 6H; 7.76 ppm: unresolved peak: 1H; 8.03 ppm: s: 1H;8.59 ppm: s: 1H.

Compound 37: NMR d₆-DMSO (300 MHz): 2.41 ppm: s: 6H; 2.63-2.68 ppm:unresolved peak: 4H; 2.89 ppm: t (J=5.8): 2H; 3.77-3.82 ppm: unresolvedpeak: 4H; 4.08 ppm: unresolved peak: 6H; 4.24 ppm: t (J=5.8): 2H;6.95-8.05 ppm: unresolved peak: 7H;

Compound 42: NMR d₆-DMSO (200 MHz): 2.41 ppm: s: 3H; 3.7-4.5 ppm: bs:1H; 3.97 ppm: s: 3H; 4.07 ppm: s: 3H; 6.65 ppm: d: 1H; 7-7.3 ppm:unresolved peak: 4H; 7.4 ppm: d: 1H; 7.7 ppm: s: 1H; 8.25 ppm: s: 1H.

Compound 46: NMR d₆-DMSO (300 MHz): 2.5 ppm: s: 3H; 3.7 ppm: s: 3H; 7.1ppm: d: 1H; 7.3-7.5 ppm: unresolved peak: 3H; 7.7 ppm: d: 2H; 8.1 ppm:s: 1H; 11.9 ppm: s: 1H.

Compound 47: NMR CDCl₃ (300 MHz): 1.45 ppm: s: 9H; 2.5 ppm: s: 3H; 4.1ppm: s: 6H; 6.7 ppm: d: 1H; 7.2 ppm: d: 1H; 7.3 ppm: d: 1H; 7.5 ppm: d:1H; 7.6 ppm: d: 1H; 8 ppm: s: 1H.

Compound 50: NMR CDCl₃ (300 MHz): 1.7 ppm: unresolved peak: 2H; 2.5 ppm:s: 3H; 4.1 ppm: s: 6H; 7.1 ppm: d: 1H; 7.3 ppm: unresolved peak: 2H; 7.4ppm: t: 1H; 7.6 ppm: unresolved peak: 2H; 7.7 ppm: s: 1H; 8.1 ppm: s:1H.

Compound 55: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.69 ppm: s: 6H;3.83 ppm: s: 6H; 7.03 ppm: d: 1H; 7.11 ppm: s: 2H; 7.33 ppm: d: 1H; 7.71ppm: s: 1H; 8.37 ppm: s: 1H; 11.86 ppm: s: 1H.

Compound 58: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.70 ppm: s: 3H;7.05 ppm: d: 1H; 7.3 ppm: d: 1H; 7.73 ppm: s: 1H; 7.8 ppm: d: 2H; 8.03ppm: d: 2H; 8.54 ppm: s: 1H; 12 ppm: s: 1H.

Compound 59: NMR d₆-DMSO (300 MHz): 2.40 ppm: s: 3H; 3.67 ppm: s: 3H;7.02-7.06 ppm: unresolved peak: 1H; 7.24-7.28 ppm: unresolved peak: 1H;7.34 ppm: d: 1H; 7.42-7.47 ppm: unresolved peak: 2H; 7.63 ppm: s: 1H;8.1 ppm: s: 1H; 11.95 ppm: bs: 1H.

Compound 61: NMR d₆-DMSO (300 MHz): 2.40 ppm: s: 3H; 3.25 ppm: s: 6H;7.02 ppm: d: 1H; 7.23-7.36 ppm: unresolved peak: 3H; 7.61-7.68 ppm:unresolved peak: 3H [or 7.05 ppm: d (J=8.1): 1H; 7.35 ppm: d (J=8.1):1H; 7.73 ppm: s: 1H; 7.78 ppm: unresolved peak: 4H]; 8.3 ppm: s: 1H.

Compound 62: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.70 ppm: s: 3H;3.88 ppm: s: 3H; 7.05-8.50 ppm: unresolved peak: 8H; 11.97 ppm: s: 1H.

Compound 63: NMR d₆-DMSO (300 MHz): 2.41 ppm: s: 3H; 3.66 ppm: s: 3H;6.75-9.80 ppm: unresolved peak: 8H; 11.87 ppm: s: 1H.

Compound 64: NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.67 ppm: s: 3H;4.88 ppm: unresolved peak: 2H; 6.47-8.16 ppm: unresolved peak: 8H [or6.49 ppm: d (J=7.5): 1H; 6.84 ppm: d (J=7.5): 1H; 6.92-7.15 ppm:unresolved peak: 3H; 7.34 ppm: d (J=8.1): 1H; 7.65 ppm: unresolved peak;1H; 8.18 ppm: unresolved peak: 1H]; 11.82 ppm: unresolved peak: 1H.

Compound 65: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.707 ppm: s: 3H;7.04-8.47 ppm: unresolved peak: 8H; 11.95 ppm: s: 1H.

Compound 73: NMR d₆-DMSO (300 MHz): 2.3 ppm: s: 3H; 4 ppm: s: 3H; 4.1ppm: s: 3H; 6.8 ppm: d: 1H; 6.9 ppm: s: 1H; 7.2 ppm: d: 1H; 7.3 ppm: d:1H; 7.5 ppm: d: 1H; 7.7 ppm: s: 1H; 8.1 ppm: s: 1H; 9.9 ppm: bs: 1H.

Compound 77: NMR d₆-DMSO (200 MHz): 2.4 ppm: s: 3H; 3.7 ppm: s: 3H; 3.8ppm: s: 6H; 6.9 ppm: d: 1H; 7 ppm: d: 1H; 7.2-7.3 ppm: unresolved peak:3H; 7.4 ppm: s: 1H; 8.3 ppm: s: 1H.

Compound 80: NMR d₆-DMSO+TFA (200 MHz): 2.4 ppm: s: 3H; 2.8 ppm: s: 3H;3.8 ppm: s: 3H; 4.3-4.5 ppm: dd: 2H; 7.1 ppm: d: 1H; 7.3-7.6 ppm:unresolved peak: 3H; 7.7 ppm: s: 1H; 7.9 ppm: d: 1H; 8 ppm: s: 1H; 8.4ppm: s: 1H.

Compound 81: NMR d₆-DMSO (200 MHz): 2.3 ppm: s: 3H; 3.6 ppm: s: 3H; 4.4ppm: d: 2H; 5.1 ppm: unresolved peak: 1H; 7 ppm: d: 1H; 7.15-7.3 ppm:unresolved peak: 3H; 7.58-7.7 ppm: unresolved peak: 3H; 8.2 ppm: s: 1H;11.8-12 ppm: bs: 1H.

Compound 82: NMR d₆-DMSO (200 MHz): 2.4 ppm: s: 3H; 3.6 ppm: s: 3H; 3.8ppm: s: 3H; 6.95 ppm: d: 1H; 7.05 ppm: d: 1H; 7.15 ppm: d: 1H; 7.6-7.8ppm: unresolved peak: 2H; 8 ppm: s: 1H; 8.3 ppm: s: 1H; 11.8 ppm: s: 1H.

Compound 85: NMR d₆-DMSO (200 MHz): 2.3 ppm: s: 3H; 2.6 ppm: d: 3H; 3.8ppm: s: 3H; 5.2 ppm: s: 2H; 7 ppm: d: 1H; 7.3 ppm: d: 1H; 7.4 ppm:unresolved peak: 2H; 7.6 ppm: s: 2H; 8.1 ppm: s: 1H; 8.4 ppm: d: 1H.

Compound 87: NMR d₆-DMSO/TFA (200 MHz): 2.4 ppm: s: 3H; 3.6 ppm: s: 3H;3.95 ppm: s: 3H; 7 ppm: d: 1H; 7.15-7.35 ppm: unresolved peak: 2H; 7.65ppm: s: 1H; 8.05 ppm: s: 1H; 8.1 ppm: s: 1H; 8.45 ppm: s: 1H.

Compound 88: NMR d₆-DMSO/TFA (200 MHz): 4.05 ppm: s: 3H; 4.25 ppm: s:3H; 7.6-7.9 ppm: unresolved peak: 4H; 8.15 ppm: d: 1H; 8.25 ppm: s: 1H;8.5 ppm: s: 1H; 8.7 ppm: s: 1H.

Compound 94: NMR d₆-DMSO (300 MHz): 2.73 ppm: s: 3H; 4.27 ppm: s: 6H;5.02 ppm: s: 2H; 7.09-8.26 ppm: unresolved peak: 8H.

Compound 97: NMR d₆-DMSO/TFA (200 MHz): 2.4 ppm: s: 3H; 2.95 ppm: t: 2H;4 ppm: s: 3H; 4.6 ppm: t: 2H; 7.2 ppm: d: 1H; 7.4-7.7 ppm: unresolvedpeak: 3H; 7.75 ppm: s: 2H; 8.2 ppm: s: 1H.

Compound 98: NMR d₆-DMSO/TFA (200 MHz): 2.4 ppm: s: 3H; 3.6 ppm: s: 3H;3.7 ppm: s: 3H; 3.8 ppm: s: 3H; 6.95 ppm: s: 1H; 7-7.1 ppm: unresolvedpeak: 2H; 7.35 ppm: d: 1H; 7.6 ppm: s: 1H; 8.05 ppm: s: 1H.

Compound 99: NMR d₆-DMSO/TFA (200 MHz): 2.3 ppm: s: 3H; 3.7 ppm: s: 3H;3.75 ppm: s: 3H; 3.9 ppm: s: 3H; 4.05 ppm: s: 3H; 6.85 ppm: s: 1H; 7ppm: s: 1H; 7.05 ppm: s: 1H; 7.4 ppm: d: 1H; 7.6 ppm: s: 1H; 8 ppm: s:1H.

Compound 100: NMR d₆-DMSO/TFA (200 MHz): 2.4 ppm: s: 3H; 3.65 ppm: s:3H; 3.7 ppm: s: 3H; 3.8 ppm: s: 3H; 6.95 ppm: s: 1H; 7.05 ppm: d: 1H;7.2 ppm: s: 1H; 7.35 ppm: d: 1H; 7.65 ppm: s: 1H; 8.05 ppm: s: 1H.

Compound 101: NMR d₆-DMSO/TFA (200 MHz): 2.2 ppm: s: 3H; 2.3 ppm: s: 3H;2.4 ppm: s: 3H; 3.75 ppm: s: 3H; 7-7.2 ppm: unresolved peak: 4H; 7.4ppm: d: 1H; 7.7 ppm: s: 1H; 8 ppm: s: 1H.

Compound 103: NMR d₆-DMSO/TFA (200 MHz): 2.3 ppm: s: 3H; 2.45 ppm: s:3H; 2.5 ppm: s: 3H; 3.7 ppm: s: 3H; 7.1 ppm: d: 1H; 7.2 ppm: d: 1H; 7.4ppm: d: 1H; 7.5 ppm: d: 1H; 7.6 ppm: s: 1H; 7.75 ppm: s: 1H; 8.35 ppm:s: 1H.

Compound 112: NMR d₆-DMSO (300 MHz): 2.41 ppm: s: 3H; 2.46 ppm: s: 3H;2.69-2.72 ppm: unresolved peak: 4H; 3.19-3.28 ppm: unresolved peak: 4H;3.76 ppm: s: 3H; 6.93 ppm: dd: 1H; 7.09 ppm: d: 1H; 7.15 ppm: d: 1H;7.28 ppm: d: 1H; 7.33 ppm: unresolved peak: 2H; 7.61 ppm: s: 1H; 8.19ppm: s: 1H.

Compound 114: NMR d₆-DMSO (300 MHz): 3.69 ppm: s: 3H; 7.4 ppm:unresolved peak: 4H; 7.67 ppm: d: 1H; 8.09 ppm: d: 1H; 8.29 ppm: s: 1H;12.28 ppm: s: 1H.

Compound 116: NMR d₆-DMSO (300 MHz): 2.41 ppm: s: 3H; 3.67 ppm: s: 3H;6.12 ppm: s: 2H; 7.02 ppm: s: 1H; 7.10 ppm: s: 1H; 7.19 ppm: s: 1H; 7.36ppm: d: 1H; 7.63 ppm: s: 1H; 8.05 ppm: s: 1H; 11.92 ppm: s: 1H.

Compound 117: NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.68 ppm: s: 3H;3.78 ppm: s: 6H; 6.41-8.37 ppm: unresolved peak: 7H; 11.89 ppm: s: 1H.

Compound 119: NMR d₆-DMSO (200 MHz): 2.4 ppm: s: 3H; 3.7 ppm: s: 3H;7-7.2 ppm: unresolved peak: 3H; 7.4 ppm: d: 1H; 7.7 ppm: s: 1H; 7.8 ppm:d: 2H; 8.4 ppm: s: 1H.

Compound 122: NMR d₆-DMSO (300 MHz): 2.50 ppm: s: 6H; 3.79 ppm: s: 3H;4.03 ppm: unresolved peak: 2H; 6.92-8.28 ppm: unresolved peak: 7H; 12.46ppm: s: 1H.

Compound 124: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.98 ppm: s: 3H;4.08 ppm: s: 3H; 7.06-7.16 ppm: unresolved peak: 8H.

Compound 125: NMR d₆-DMSO (300 MHz): 2.31 ppm: s: 6H; 3.69 ppm: s: 3H;6.91 ppm: s: 1H; 7.28-7.44 ppm: unresolved peak: 4H; 8.15 ppm: d: 1H;8.38 ppm: s: 1H; 12.30 ppm: s: 1H.

Compound 126: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 3.70 ppm: s: 3H;7.05-8.88 ppm: unresolved peak: 8H; 11.97 ppm: s: 1H.

Compound 128: NMR d₆-DMSO (300 MHz): 3.61 ppm: s: 3H; 3.78 ppm: s: 3H;6.83 ppm: dd: 1H; 7.33-7.48 ppm: unresolved peak: 4H; 7.66 ppm: d: 1H;8.17 ppm: s: 1H; 11.91 ppm: s: 1H.

Compound 129: NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.69 ppm: s: 3H;5.15 ppm: s: 2H; 6.93-8.36 ppm: unresolved peak: 13H; 11.88 ppm: s: 1H.

Compound 130: NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.68 ppm: s: 3H;6.67 ppm: dd: 1H; 7.02 ppm: dd: 1H; 7.03-7.24 ppm: unresolved peak: 3H;7.34 ppm: d: 1H; 7.68 ppm: s: 1H; 8.25 ppm: s: 1H; 9.26 ppm: bs: 1H;11.85 ppm: bs: 1H.

Compound 131: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 7.05-8.61 ppm:unresolved peak: 7H; 12.00 ppm: s: 1H.

Compound 134: NMR d₆-DMSO (300 MHz): 2.43 ppm: s: 3H; 4.02 ppm: s: 3H;7.06 ppm: dd: 1H; 7.29 ppm: bs: 1H; 7.35 ppm: d: 1H; 7.72 ppm: s: 1H;7.84-7.94 ppm: unresolved peak: 5H; 8.45 ppm: s: 1H.

Compound 138: NMR d₆-DMSO (300 MHz): 1.71 ppm: s: 3H; 2.44 ppm: s: 3H;2.64 ppm: s: 3H; 4.02 ppm: s: 3H; 4.20 ppm: s: 3H; 7.12 ppm: d: 1H;7.48-7.56 ppm: unresolved peak: 2H; 7.76 ppm: unresolved peak: 1H; 7.87ppm: d: 1H; 8.03 ppm: d: 1H; 8.35 ppm: unresolved peak: 1H; 8.46 ppm: s:1H.

Compound 140: NMR d₆-DMSO (300 MHz): 2.79 ppm: s: 3H; 3.69 ppm: s: 3H;6.83 ppm: t: 1H; 7.03 ppm: dd: 1H; 7.34 ppm: d: 1H; 7.66-7.80 ppm:unresolved peak: 5H; 8.27 ppm: s: 1H; 8.49 ppm: d: 1H; 9.63 ppm: s: 1H;11.84 ppm: s: 1H.

Compound 141: NMR d₆-DMSO (300 MHz): 2.45 ppm: s: 3H; 4.04 ppm: s: 3H;5.22 ppm: s: 2H; 5.87 ppm: s: 2H; 7.01-9.31 ppm: unresolved peak: 8H.

Compound 142: NMR d₆-DMSO (300 MHz): 2.21 ppm: s: 6H; 2.43 ppm: s: 3H;2.64 ppm: t: 2H; 3.99 ppm: s: 3H; 4.62 ppm: t: 2H; 6.67-8.29 ppm:unresolved peak: 8H; 9.27 ppm: s: 1H.

Compound 145: NMR d₆-DMSO/TFA (200 MHz): 2.4 ppm: s: 3H; 3.7 ppm: s: 3H;6.9-7.1 ppm: unresolved peak: 2H; 7.3-7.45 ppm: unresolved peak: 3H;7.5-7.7 ppm: unresolved peak: 2H; 8.35 ppm: s: 1H.

Compound 148: NMR d₆-DMSO (300 MHz): 2.40 ppm: s: 3H; 3.67 ppm: s: 3H;7.04 ppm: d: 1H; 7.35 ppm: unresolved peak: 2H; 7.57 ppm: dd: 1H; 7.63ppm: s: 1H; 7.77 ppm: d: 1H; 8.12 ppm: s: 1H; 11.96 ppm: s: 1H.

Compound 150: NMR d₆-DMSO (300 MHz): 2.43 ppm: unresolved peak: 2H; 2.51ppm: s: 3H; 4.10-4.30 ppm: unresolved peak: 4H; 7.17-8.20 ppm:unresolved peak: 7H.

Compound 155: NMR d₆-DMSO (300 MHz): 1.36 ppm: t(J=7.0): 3H; 4.02 ppm:s: 3H; 4.34 ppm: q(J=7.0): 2H; 5.97 ppm: s: 2H; 7.48 ppm: unresolvedpeak: 2H; 7.70 ppm: s: 1H; 7.88 ppm: d (J=8.6): 1H; 7.98 ppm: dd (J=1.5;J=8.6): 1H; 8.47 ppm: s: 1H; 8.61 ppm: s: 1H.

Compound 156: NMR d₆-DMSO (300 MHz): 1.33 ppm: t(J=7): 3H; 3.70 ppm: s:3H; 4.32 ppm: q(J=7): 2H; 7.41 ppm: unresolved peak: 2H; 7.46 ppm: d(J=8.5): 1H; 7.67 ppm: s: 1H; 7.86 ppm: d (J=8.5): 1H; 8.34 ppm: s: 1H;8.53 ppm: s: 1H; 12.46 ppm: s: 1H.

Compound 159: NMR d₆-DMSO (300 MHz): 2.42 ppm: s: 3H; 3.69 ppm: s: 3H;7.05 ppm: d (J=7.0): 1H; 7.21 ppm: d (J=7.29): 1H; 7.37 ppm: d (J=8.15):2H; 7.51 ppm: d (J=2.6): 1H; 7.54 ppm: s: 1H; 7.64 ppm: s: 1H; 8.14 ppm:s: 1H; 8.34 ppm: d (J=7.22): 2H; 10.71 ppm: s: 1H; 12.03 ppm: s: 1H.

Compound 160: NMR d₆-DMSO (300 MHz): 2.40 ppm: s: 3H; 3.17 ppm:unresolved peak: 4H; 3.66 ppm: s: 3H; 3.75 ppm: unresolved peak: 4H;6.94 ppm: dd (J=2.45; J=8.60): 1H; 7.03 ppm: unresolved peak: 2H; 7.23ppm: d (J=8.51): 1H; 7.34 ppm: d (J=8.12): 1H; 7.62 ppm: s: 1H; 8.02ppm: s: 1H; 11.87 ppm: s: 1H.

Compound 166 d₆-DMSO: 3.73 ppm: s: 3H; 3.97 ppm: s: 3H; 7.56 ppm: d: 1H;7.63 ppm: d: 1H; 7.95 ppm: d: 1H; 8.07 ppm: unresolved peak: 2H; 8.73ppm: s: 1H; 8.92 ppm: s: 1H; 12.57 ppm: s: 1H.

The compounds according to the invention have formed the subject ofpharmacological trials which make it possible to determine theiranticancer activity.

The compounds of formula (I) according to the present invention weretested in vitro on a human breast cancer cell line: the MDA-MB-231 lineavailable from the American Type Culture Collection (reference HTB26).

The antiproliferative effect is evaluated according to J. M. Derocq etal., FEBS Letters, 1998, 425, 419-425: the level of incorporation of[³H]thymidine in the DNA of the treated cells is measured afterincubating a compound of formula (I) for 96 hours. The inhibitoryconcentration 50 (IC₅₀) is defined as the concentration which inhibitscell proliferation by 50%.

The compounds according to the invention exhibit an IC₅₀ generally ofless than 10 μM with regard to the MDA-MB-231 line.

The compounds of formula (I) were also tested on another human breastcancer cell line, a “multi-drug-resistant” (MDR) line referred to asMDA-A₁. This line is described by E. Collomb, C. Dussert and P. M.Martin in Cytometry, 1991, 12(1), 15-25.

The term “multi-resistant” which describes this line means that the saidline is generally not very sensitive to the chemotherapeutic drugscommonly used and in particular to antimitotics of natural origin, suchas paclitaxel, vincristine or vinblastine.

The compounds according to the invention exhibit an IC₅₀ generally ofless than 10 μM with regard to the MDA-A₁ multi-resistant line.

The compounds according to the invention were also tested in vivo inmurine models of human tumour xenografts according to the methodsdescribed in the literature: Mooberry S. L. et al., Int. J. Cancer,2003, 104 (4), 512-521; Polin L. et al., Invest. New Drugs, 2002, 20(1), 13-22; Corbett T. H et al., Invest. New Drugs, 1999, 17 (1), 17-27.Fragments of human tumours with a diameter of 2 to 3 mm are implantedsubcutaneously in SCID (Severe Combined Immunodeficiency) mice of theBalb/C strain (Iffa-Credo, Lyons, France). When these tumours reach aweight of 50-60 mg, the compounds are administered orally orintravenously every day or every two days throughout the duration of theexperiment (20 to 40 days) at doses varying from 10 to 300 mg/kg peradministration. The weight of the tumours is estimated according to theformula: W (weight of the tumour in mg)=(a×b²)/2, where a and brespectively represent the length and the width in mm of the tumourimplant. The measurement of a and of b is carried out using a caliperrule. The antitumour effectiveness is evaluated by comparing the meanweight of the tumours in the group of animals treated with the testcompound (T) with that of the animals of the control group to which onlythe solvent of the compound has been administered (C). This measurement,expressed as % of the ratio T/C, is carried out when C reachesapproximately 1 000 mg. The compounds according to the inventiondemonstrated an in vivo antitumour activity (ratio T/C of less than100%), some very significantly with a ratio T/C of less than or equal to42%.

Thus, according to the present invention, it is apparent that thecompounds of formula (I) inhibit the proliferation of tumour cells,including those of cells exhibiting multi-resistance. It is thusapparent that the compounds according to the invention have ananticancer activity.

Thus, according to another of its aspects, a subject-matter of theinvention is medicaments which comprise a compound of formula (I) or anaddition salt of the latter with a pharmaceutically acceptable acid oralso a hydrate or a solvate of the compound of formula (I).

These medicaments find their use in therapeutics, in particular in thetreatment of or protection from diseases caused or exacerbated by theproliferation of tumour cells.

These compounds, as inhibitor of the proliferation of tumour cells, areof use in the treatment of solid tumours, both primary and metastaticsolid tumours, carcinomas and cancers, in particular: breast cancer;lung cancer; cancer of the small intestine, cancer of the colon and ofthe rectum; cancer of the respiratory tract, of the oropharynx and ofthe hypopharynx; cancer of the oesophagus; liver cancer, stomach cancer,cancer of the bile ducts, cancer of the gall bladder, cancer of thepancreas; cancers of the urinary tract, including kidney, urothelium andbladder; cancers of the female genital tract, including cancer of theuterus, cervix and ovaries, choriocarcinoma and trophoblastic cancer;cancers of the male genital tract, including cancer of the prostate,seminal vesicles and testicles, tumours of the germinal cells; cancersof the endocrine glands, including cancer of the thyroid, pituitarygland and adrenal glands; skin cancers, including haemangiomas,melanomas and sarcomas, including Kaposi's sarcoma; tumours of thebrain, nerves, eyes and meninges, including astrocytomas, gliomas,glioblastomas, retinoblastomas, neurinomas, neuroblastomas, schwannomasand meningiomas; solid tumours resulting from haematopoietic malignanttumours, including leukaemias, chloromas, plasmacytomas, fungoidmycosis, T-cell lymphoma or leukaemia, non-Hodgkin's lymphoma, malignanthaemopathies and myelomas.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions comprisean effective dose of at least one compound according to the invention,or a pharmaceutically acceptable salt, a hydrate or solvate of the saidcompound, and at least one pharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical form andthe method of administration desired, from the usual excipients whichare known to a person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intra-tracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its optional salt, solvate orhydrate, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and man for theprophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms comprise forms by the oralroute, such as tablets, soft or hard gelatin capsules, powders, granulesand oral solutions or suspensions, sublingual, buccal, intra-tracheal,intraocular or intranasal, by inhalation, administration forms, topical,transdermal, subcutaneous, intramuscular or intravenous administrationforms, rectal administration forms and implants. Use may be made, forthe topical application, of the compounds according to the invention increams, gels, ointments or lotions.

The compounds of formula (I) above can be used at daily doses of 0.002to 2 000 mg per kilogram of body weight of the mammal to be treated,preferably at daily doses of 0.1 to 300 mg/kg. In man, the dose canpreferably vary from 0.02 to 10 000 mg per day, more particularly from 1to 3 000 mg, depending on the age of the subject to be treated or thetype of treatment: prophylactic or curative.

There may be specific cases where higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to usual practice, the dosage appropriate to each patient isdetermined by the doctor according to the method of administration andthe weight and response of the said patient.

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or its hydrates or solvates.

According to the present invention, the compound or compounds of formula(I) can be administered in combination with one (or more) anticanceractive principle(s), in particular antitumour compounds, such asalkylating agents, such as alkylsulphonates (busulfan), dacarbazine,procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil),cyclophosphamide or ifosfamide; nitrosoureas, such as carmustine,lomustine, semustine or streptozocin; antineoplastic alkaloids, such asvincristine or vinblastine; taxanes, such as paclitaxel or taxotere;antineoplastic antibiotics, such as actinomycin; intercalating agents,antineoplastic antimetabolites, folate antagonists or methotrexate;purine synthesis inhibitors; purine analogues, such as mercaptopurine or6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors,capecitabine or pyrimidine analogues, such as fluorouracil, gemcitabine,cytarabine and cytosine arabinoside; brequinar; topoisomeraseinhibitors, such as camptothecin or etoposide; anticancer hormonalagonists and antagonists, including tamoxifen; kinase inhibitors,imatinib; growth factor inhibitors; antiinflammatories, such as pentosanpolysulphate, corticosteroids, prednisone or dexamethasone;antitopoisomerases, such as etoposide, anthracyclines, includingdoxorubicin, bleomycin, mitomycin and mithramycin; anticancer metalcomplexes, platinum complexes, cisplatin, carboplatin or oxaliplatin;interferon-alpha, triphenyl thiophosphoramide or altretamine;antiangiogenic agents; thalidomide; immunotherapy adjuvants; orvaccines.

1. A method for the treatment of breast cancer, which comprisesadministering to a patient suffering from said disease an effective doseof a compound of formula (I):

in which: R₁ represents a hydrogen atom, a (C₁-C₄)alkyl group or a(CH₂)_(n)OH, (CH₂)_(n)—O-tetrahydropyran-2-yl, (CH₂)_(n)NR′₆R′₇,(CH₂)_(n)CN, (CH₂)_(n)CO₂(C₁-C₄)alk or (CH₂)_(n)CONR₆R₇ group; R₂represents a hydrogen atom or a (C₁-C₄)alkyl group; R₃ represents aphenyl monosubstituted by a hydroxyl, hydroxymethyl, carboxyl,(C₁-C₄)alkanoyl, azido, (C₁-C₄)alkoxycarbonyl, hydroxyiminomethyl,(C₁-C₄)alkylsulphonyl, trifluoromethyl, thiol, (C₁-C₄)alkylthio or cyanogroup or by a (CH₂)_(m)NR′₇R₁₀, CONR₆R₈ or O(CH₂)_(n)R₉ group; a phenylsubstituted by 2 to 5 identical or different substituents chosen from ahalogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, hydroxymethyl,(C₁-C₄)alkoxy, carboxyl, (C₁-C₄)alkanoyl, azido, (C₁-C₄)alkoxycarbonyl,hydroxyiminomethyl, thiol, (C₁-C₄)alkylthio or (C₁-C₄)alkylsulphonylgroup, or a phenyl or cyano, or by a (CH₂)_(m)NR′₇R₁₀, CONR₆R₈ orO(CH₂)_(n)R₉ group; or R₃ represents a benzodioxolyl group which isunsubstituted or substituted on the phenyl by a halogen atom; R₄ and R₅are identical or different and each independently represent a hydrogenor halogen atom or a hydroxyl, (C₁-C₄)alkyl, trifluoromethyl, phenyl,cyano, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl or (C₁-C₄)alkylsulphonylgroup or an O—(CH₂)NR₆R₇ or (CH₂)_(n)NR₆R₇ group; R₆ represents hydrogenor a (C₁-C₄)alkyl group; R₇ represents hydrogen or a (C₁-C₄)alkyl group;or R₆ and R₇, together with the nitrogen atom to which they are bonded,form a heterocyclic radical chosen from: piperidyl, morpholinyl,pyrrolidinyl, piperazinyl or 4-methylpiperazin-1-yl; R′₆ representshydrogen or a (C₁-C₄)alkyl group; R′₇ represents hydrogen or a(C₁-C₄)alkyl group; or R′₆ and R′₇, together with the nitrogen atom towhich they are bonded, form a heterocyclic radical chosen frommorpholinyl or pyrrolidinyl; R₈ represents hydrogen, a (C₁-C₄)alkylgroup or a —(CH₂)_(n)NR₆R₇ group; or R₆ and R₈, together with thenitrogen atom to which they are bonded, form a heterocyclic radicalchosen from: piperidyl, morpholinyl, pyrrolidinyl, piperazinyl or4-methylpiperazin-1-yl; R₉ represents a phenyl radical or an amino,morpholin-4-yl, cyano or (C₁-C₄)alkoxycarbonyl group; R₁₀ represents R′₆or a phenyl, pyridyl or pyrimidinyl group or a (CH₂)_(n)NR′₆R′₇ group;or R′₇ and R₁₀, together with the nitrogen atom to which they arebonded, form a heterocyclic radical chosen from piperazinyl or4-methylpiperazin-1-yl; n represents 1, 2 or 3; m represents 0 or 1; Alkrepresents an alkyl; or a pharmaceutically acceptable salt thereof. 2.The method according to claim 1, which comprises administering to apatient an effective dose of a compound of formula (I):

wherein: R₁ represents a hydrogen atom or a methyl, cyanomethyl,(C₁-C₄)alkoxycarbonylmethyl, aminomethyl, aminoethyl, aminopropyl orpyrrolidinoethyl group; and R₂ represents a methyl group; and R₃represents a phenyl monosubstituted by a hydroxyl,(C₁-C₄)alkoxycarbonyl, methylsulphonyl, trifluoromethyl, methylthio,cyanomethoxy, aminoethoxy, acetyl, hydroxymethyl, cyano, amino, azido,aminomethyl or hydroxyiminomethyl group or a (CH₂)_(m)NR′₇R₁₀ group inwhich R′₇ represents a hydrogen atom or a methyl, R₁₀ represents ahydrogen atom or a phenyl, pyridyl or pyrimidinyl group or R′₇ and R₁₀,together with the nitrogen atom to which they are bonded, form apiperazin-1-yl or 4-methylpiperazin-1-yl group, and m represent zero orone; or R₃ represents a phenyl substituted by 2 to 3 identical ordifferent subsituents chosen from a halogen atom, a methyl, methoxy,methylthio, triflouromethyl, hydroxyl, (C₁-C₄)alkoxycarbonyl,methylsulphonyl, cyanomethoxy, aminoethoxy, acetyl, hydroxymethyl,cyano, amino, azido, aminomethyl or hydroxyiminomethyl group or a(CH₂)_(m)NR′₇R₁₀ group in which R′₇ represents a hydrogen atom or amethyl, R₁₀ represents a Hydrogen atom or a phenyl, pyridyl orpyrimidinyl group or R′₇ and R₁₀, together with the nitrogen atom towhich they are bonded, form a piperazin-1-yl or 4-methylpiperazin-1-ylgroup, and m represents zero or one; or R₃ represents a benzodioxolylgroup which is unsubstituted or substituted on the phenyl by a halogenatom; and/or R₄ represents a halogen atom or a methyl, methoxy or(C₁-C₄)alkoxycarbonyl group; and/or R₅ represents a hydrogen atom or amethyl group; or a pharmaceutically acceptable salt thereof.
 3. Themethod according to claim 1, wherein the compound is selected from thegroup consisting of:3-(2,4-dimethoxyphenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6carboxylicacid;3-(2,4-dimethoxyphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(3-hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]-indol-3-yl)benzonitrile;3-(4-aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(6-chloro-1,3-benzodioxol-5-yl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;1,6-dimethyl-1,9-dihydro-3-(phenylaminophenyl)-2H-pyrido[2,3-b]indol-2-one;6-bromo-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;1,6-dimethyl-3-(3-(trifluoromethyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;1,6-dimethyl-3-(3-(pyridin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;1,6-dimethyl-3-(3-(pyrimidin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(3-acetylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;and methyl9-(cyanomethyl)-3-(2,4-dichlorophenyl)-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylate;or a pharmaceutically acceptable salt thereof.
 4. The method accordingto claim 1, wherein the compound is3-(2,4-dimethoxyphenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylic acid.
 5. The method according to claim 1,wherein the compound is3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.6. The method according to claim 1, wherein the compound is1,6-dimethyl-3-(3-(pyridine-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-]indol-2-one. 7.The method according to claim 1, wherein the compound is1,6-dimethyl-3-(3-(pyrimidin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.